1N-alkyl-n-arylpyrimidinamines and derivatives thereof

ABSTRACT

The present invention provides novel compounds, compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer&#39;disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula:                    
     wherein R 1 , R 3 , R 4 , R 5 , Z, Y, V, X, X′, J, K, L, and M are as defined herein.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

This is a continuation, of application Ser. No. 08/315,660 filed Sep.29, 1994 now abandoned which is a continuation-in-part of U.S. patentapplication Ser. No. 08/297,274 filed, Aug. 26, 1994, now abandoned,which is a continuation-in-part of U.S. patent application Ser. No.08/134,209, filed Oct. 12, 1993 now abandoned. The disclosures of theseearlier filed applications are hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds, compounds andpharmaceutical compositions thereof, and to methods of using same in thetreatment of psychiatric disorders and neurological diseases includingmajor depression, anxiety-related disorders, post-traumatic stressdisorder, supranuclear palsy eating feeding disorders, irritable bowelsyndrome, immune suppression, Alzheimer's disease, gastrointestinaldiseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drugaddiction, inflammatory disorders, and fertility problems.

2. Description of the Related Art

Corticotropin releasing factor (herein referred to as CRF), a 41 aminoacid peptide, is the primary physiological regulator ofproopiomelanocortin (POMC)-derived peptide secretion from the anteriorpituitary gland (J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851(1983); W. Vale et al., Science 213:1394 (1981)). In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain (W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)). There isalso evidence demonstrating that CRF may also play a significant role inintegrating the response of the immune system to physiological,psychological, and immunological stressors (J. E. Blalock, PhysiologicalReviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)).

Clinical data have demonstrated that CRF may have implications inpsychiatric disorders and neurological diseases including depression,anxiety-related disorders and eating disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system (for reviewsee E. B. De Souza, Hosp. Practice 23:59 (1988)).

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals (C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Bankiet al. Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol.Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry 25:355(1989)). Furthermore, the density of CRF receptors is significantlydecreased in the frontal cortex of suicide victims, consistent with ahypersecretion of CRF (C. B. Nemeroff et al., Arch. Gen. Psychiatry45:577 (1988)). In addition, there is a blunted adrenocorticotropin(ACTH) response to CRF (i.v. administered) observed in depressedpatients (P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F.Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold etal., New Eng. J. Med. 314:1129 (1986)). Preclinical studies in rats andnon-human primates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression (R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)). Thereis preliminary evidence that tricyclic antidepressants can alter CRFlevels and thus modulate the number of CRF receptors in brain(Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)).

There has also been a role postulated for CRF in the etiology ofanxiety-related disorders. CRF produces anxiogenic effects in animalsand interactions between benzodiazepine/non-benzodiazepine anxiolyticsand CRF have been demonstrated in a variety of behavioral anxiety models(D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.Dunn Regul. Peptides 16:83 (1986)). Preliminary studies using theputative CRF receptor antagonist α-helical ovine CRF (9-41) in a varietyof behavioral paradigms demonstrate that the antagonist produces“anxiolytic-like” effects that are qualitatively similar to thebenzodiazepines (C. W. Berridge and A. J. Dunn Horm. Behav. 21:393(1987), Brain Research Reviews 15:71 (1990)). Neurochemical, endocrineand receptor binding studies have all demonstrated interactions betweenCRF and benzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test (K. T. Britton etal., Psychopharmacology 86:170 (1985); K. T. Britton et al.,Psychopharmacology 94:306 (1988)) and in the acoustic startle test (N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)) in rats. Thebenzodiazepine receptor antagonist (Ro15-1788), which was withoutbehavioral activity alone in the operant conflict test, reversed theeffects of CRF in a dose-dependent manner while the benzodiazepineinverse agonist (FG7142) enhanced the actions of CRF (K. T. Britton etal., Psychopharmacology 94:306 (1988)).

The mechanisms and sites of action through which the standardanxiolytics and antidepressants produce their therapeutic effects remainto be elucidated. It has been hypothesized, however, that they areinvolved in the suppression of the CRF hypersecretion that is observedin these disorders. Of particular interest is that preliminary studiesexamining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁)in a variety of behavioral paradigms have demonstrated that the CRFantagonist produces “anxiolytic-like” effects qualitatively similar tothe benzodiazepines (for review, see G. F. Koob and K. T. Britton, In:Corticotropin-Releasing Factor: Basic and Clinical Studies of aNeuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p.221(1990)).

In order to study these specific cell-surface receptor proteins,compounds must be identified that can interact with the CRF receptor ina specific manner dictated by the pharmacological profile of thecharacterized receptor. Toward that end, there is evidence that thedirect CRF antagonist compounds and compositions of this invention,which can attenuate the physiological responses to stress-relateddisorders, will have potential therapeutic utility for the treatment ofdepression and anxiety-related disorders. All of the aforementionedreferences are hereby incorporated by reference.

U.S. Pat. Nos. 4,788,195 and 4,876,252 teach the synthesis of compoundswith the general formula (A):

The utility of these compounds is described as treatment of asthma,allergic diseases, inflammation, and diabetes in mammals.

PCT application WO 89/01938 describes the synthesis and utility ofcompounds with the formula (B):

These compounds can be utilized in the treatment of neurologic diseases,having an effect of regenerating and repairing nerve cells and improvingand restoring learning and memory.

U.S. Pat. No. 4,783,459 describes the utility and synthesis of compoundswith the following general formula (C):

The compounds have activity as fungicides, especially against fungaldiseases of plants.

U.S. Pat. No. 4,992,438 discloses the utility and synthesis of compoundswith the following general formula:

The utility of these compounds is described as fungicides with a broadspectrum activity against plant pathogenic fungi.

European Patent Application 0 013 143 A2 discloses the utility andsynthesis of compounds with the following general formula:

These compounds are described as pre- and post-emergence herbicides.

U.S. Pat. No. 5,063,245 discloses a method of producing CRF antagonismwith compounds with the general formulae:

PCT application WO 91/18887 discloses compounds of the general formula:

wherein R² may be C₁-C₄ alkyl and R³ may be substituted phenyl, saidcompounds being useful for the inhibition of gastric acid secretion.

European patent application EP 0588762 A1 discloses compounds of thegeneral formula:

wherein R⁴ may be C₁-C₃ alkyl, said compounds being useful as proteinkinase C inhibitors and antitumor agents. The application also generallydiscloses the use of these compounds for the treatment of AIDS,atherosclerosis, and cardiovascular and central nervous systemdisorders.

European patent application EP 336494 A2 discloses compounds of thegeneral formula:

wherein X may be N—R⁴ and R⁴ may be (un)substituted alkyl, saidcompounds being useful as herbicides.

U.S. Pat. No. 3,988,338 discloses compounds of the general formula:

wherein R″″ may be an optionally substituted phenyl, said compoundshaving anticytokinin activity.

European patent application EP 0563001 A1 discloses compounds of thegeneral formula:

said compounds having claimed utility for the treatment of psychosis,depression, and convulsive disorders.

European patent application EP 0155911 A1 discloses compounds of thegeneral formula:

wherein R³ may be substituted phenyl, said compounds being useful asherbicides.

Australian patent AU 8425873 A discloses compounds of the generalformula:

wherein R² may be a substituted phenyl group, said compounds beinguseful as antiulcer agents.

Eswaran et al, Org. Prep. Proced. Int. 24(1):71-3, (1992), discloses theuse of related 5,7-diazaindoles as synthetic intermediates. El-Bayoukiet al, J. Heterocycl. Chem. 22(3):853-6, (1985) discloses the use ofrelated 5,7-diazaisoindazoles as synthetic intermediates.

The compounds and methods of the present invention provide themethodology for the production of specific high-affinity compoundscapable of inhibiting the action of CRF at its receptor protein in thebrain. These compounds should be useful in the treatment of a variety ofneurodegenerative, neuropsychiatric and stress-related disorders such asirritable bowel syndrome, immune suppression. Alzheimer's disease,gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawalsymptoms, drug addiction, inflammatory disorders, and fertilityproblems. It is further asserted that this invention may providecompounds and pharmaceutical compositions suitable for use in such amethod. Further advantages of this invention will be clear to oneskilled in the art from the reading of the description that follows.

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods of use andpreparation of N-alkyl-N-aryl-pyrimidinamines and derivatives thereof.These compounds interact with and have antagonist activity at the CRFreceptor and would thus have some therapeutic effect on psychiatricdisorders and neurological diseases including major depression,anxiety-related disorders, post-traumatic stress and eating disorders,supranuclear palsy, irritable bowel syndrome, immune suppression,Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drugand alcohol withdrawal symptoms, drug addiction, inflammatory disorders,and fertility problems.

Novel compounds of this invention include compounds of formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein Y isCR^(3a), N, or CR²⁹;

when Y is CR^(3a) or N:

R¹ is independently selected at each occurrence from the groupconsisting of C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halogen, C₁-C₂haloalkyl, NR⁶R⁷, OR⁸, and S(O)_(n)R⁸;

R³ is C₁-C₄ alkyl, aryl, C₃-C₆ cycloalkyl, C₁-C₂ haloalkyl, halogen,nitro, NR⁶R⁷, OR⁸, S(O)_(n)R⁸, C(═O)R⁹, C(═O)NR⁶R⁷, C(═S)NR⁶R⁷,—(CHR¹⁶)_(k)NR⁶R⁷, (CH₂)_(k)OR⁸, C(═O)NR¹⁰CH(R¹¹)CO₂R¹²,—C(OH)(R²⁵)(R^(25a)), —(CH₂)_(p)S(O)_(n)-alkyl, —(CHR¹⁶)R²⁵,—C(CN)(R²⁵)(R¹⁶) provided that R²⁵ is not —NH-containing rings,—C(═O)R²⁵, —CH(CO₂R¹⁶)₂, NR¹⁰C(═O)CH(R¹¹)NR¹⁰R¹², NR¹⁰CH(R¹¹)CO₂R¹²;substituted C₁-C₄ alkyl, substituted C₂-C₄ alkenyl, substituted C₂-C₄alkynyl, substituted C₁-C₄ alkoxy, aryl-(substituted C₁-C₄) alkyl,aryl-(substituted C₁-C₄) alkoxy, substituted C₃-C₆ cycloalkyl,amino-(substituted C₁-C₄) alkyl, substituted C₁-C₄ alkylamino, wheresubstitution by R²⁷ can occur on any carbon containing substituent;2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl,4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, phenyl, 1H-indazolyl,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl,carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinylbenzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl,triazinyl, xanthenyl; or 1-tetrahydroquinolinyl or2-tetrahydroisoquinolinyl either of which can be substituted with 0-3groups chosen from keto and C₁-C₄ alkyl;

J, K, and L are independently selected at each occurrence from the groupof N, CH, and CX′;

M is CR⁵ or N;

V is CR^(1a) or N;

Z is CR² or N;

R^(1a), R², and R^(3a) are independently selected at each occurrencefrom the group consisting of hydrogen, halo, halomethyl, C₁-C₃ alkyl,and cyano;

R⁴ is (CH₂)_(m)OR¹⁶, C₁-C₄ alkyl, allyl, propargyl, (CH₂)_(m)R¹³, or—(CH₂)_(m)OC(O)R¹⁶;

X is halogen, S(O)₂R⁸, SR⁸, halomethyl, —(CH₂)_(p)OR⁸, —OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, —C(═O)R⁸, C₁-C₆ alkyl, C₄-C₁₀ cycloalkylalkyl,C₁-C₁₀alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀alkoxy, aryl-(C₂-C₁₀)-alkyl, C₃-C₆cycloalkyl, aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

X′ is independently selected at each occurrence from the groupconsisting of hydrogen, halogen, S(O)_(n)R⁸, halomethyl,—(CHR¹⁶)_(p)OR⁸, cyano, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀)-alkyl,C₃-C₆ cycloalkyl, aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, and —C(═O)NR¹⁴R¹⁵, wheresubstitution by R¹⁸ can occur on any carbon containing substituents;

R⁵ is halo, —C(═NOR¹⁶)—C₁-C₄-alkyl, C₁-C₆ alkyl, C₁-C₃ haloalkyl,—(CHR¹⁶)_(p)OR⁸, —(CHR¹⁶)_(p)S(O)_(n)R⁸, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃ 14 C₆cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl-(C₂-C₁₀)-alkyl,aryl-(C₁-C₁₀)-alkoxy, cyano, C₃-C₆ cycloalkoxy, nitro,amino-(C₁-C₁₀)-alkyl, thio-(C₂-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵, where substitution by R¹⁸ can occur onany carbon containing substituents;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy,(C₄-C₁₂)-cycloalkylalkyl, —(CH₂)_(k)R¹³, (CHR¹⁶)_(p)OR⁸,—(C₁-C₆alkyl)-aryl, heteroaryl, aryl, —S(O)₂-aryl or —(C₁-C₆alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups areoptionally substituted with 1-3 groups selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, nitro, carboxy,CO₂(C₁-C₆ alkyl), cyano, and S(O)_(z)—(C₁-C₆-alkyl); or can be takentogether to form —(CH₂)_(q)A(CH₂)_(r)—, optionally substituted with 0-3R¹⁷; or, when considered with the commonly attached nitrogen, can betaken together to form a heterocycle, said heterocycle being substitutedon carbon with 1-3 groups consisting of hydrogen, C₁-C₆ alkyl, hydroxy,or C₁-C₆ alkoxy;

A is CH₂, O, NR²⁵, C(═O), S(O)_(n), N(C(═O)R¹⁷), N(R¹⁹), C(H)(NR¹⁴R¹⁵),C(H)(OR²⁰), C(H)(C(═O)R²¹), or N(S(O)_(n)R²¹);

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen; C₁-C₆ alkyl; —(C₄-C₁₂) cycloalkylalkyl;(CH₂)_(t)R²²; C₃-C₁₀ cycloalkyl; —NR⁶R⁷; aryl; —NR¹⁶(CH₂)_(n)NR⁶R⁷;—(CH₂)_(k)R²⁵; and (CH₂)_(t)heteroaryl or (CH₂)_(t)aryl, either of whichcan optionally be substituted with 1-3 groups selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, nitro, carboxy,CO₂(C₁-C₆ alkyl), cyano, and S(O)_(z)(C₁-C₆-alkyl);

R⁹ is independently selected at each occurrence from R¹⁰, hydroxy, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, aryl substituted with 0-3 R¹⁸,and —(C₁-C₆ alkyl)-aryl substituted with 0-3 R¹⁸;

R¹⁰, R¹⁶, R²³, and R²⁴ are independently selected at each occurrencefrom hydrogen or C₁-C₄ alkyl;

R¹¹ is C₁-C₄ alkyl substituted with 0-3 groups chosen from thefollowing: keto, amino, sulfhydryl, hydroxyl, guanidinyl,p-hydroxyphenyl, imidazolyl, phenyl, indolyl, indolinyl,

or, when taken together with an adjacent R¹⁰, are (CH₂)_(t);

R¹² is hydrogen or an appropriate amine protecting group for nitrogen oran appropriate carboxylic acid protecting group for carboxyl;

R¹³ is independently selected at each occurrence from the groupconsisting of CN, OR¹⁹, SR¹⁹, and C₃-C₆ cycloalkyl;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₄-C₁₀ cycloalkyl-alkyl, and R¹⁹;

R¹⁷ is independently selected at each occurrence from the groupconsisting of R¹⁰, C₁-C₄ alkoxy, halo, OR²³, SR²³, NR²³R²⁴, and (C₁-C₆)alkyl (C₁-C₄) alkoxy;

R¹⁸ is independently selected at each occurrence from the groupconsisting of R¹⁰, hydroxy, halogen, C₁-C₂ haloalkyl, C₁-C₄ alkoxy,C(═O)R²⁴, and cyano;

R¹⁹ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, (CH₂)_(w)R²², and arylsubstituted with 0-3 R¹⁸;

R²⁰ is independently selected at each occurrence from the groupconsisting of R¹⁰, C(═O)R³¹, and C₂-C₄ alkenyl;

R²¹ is independently selected at each occurrence from the groupconsisting of R¹⁰, C₁-C₄ alkoxy, NR²³R²⁴, and hydroxyl;

R²² is independently selected at each occurrence from the groupconsisting of cyano, OR²⁴, SR²⁴, NR²³R²⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,—S(O)_(n)R³¹, and —C(═O)R²⁵;

R²⁵, which can be optionally substituted with 0-3 R¹⁷, is independentlyselected at each occurrence from the group consisting of phenyl,pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl,azetidinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl,benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinylbenzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, quinuclidinyl, β-carbolinyl, tetrahydrofuranyl,tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl;and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of whichcan be substituted with 0-3 groups chosen from keto and C₁-C₄ alkyl;

R^(25a), which can be optionally substituted with 0-3 R¹⁷, isindependently selected at each occurrence from the group consisting of Hand R²⁵;

R²⁷ is independently selected at each occurrence from the groupconsisting of C₁-C₃ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ alkoxy,aryl, nitro, cyano, halogen, aryloxy, and heterocycle optionally linkedthrough O;

R³¹ is independently selected at each occurrence from the groupconsisting of C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₀ cycloalkyl-alkyl,and aryl-(C₁-C₄) alkyl;

k, m, and r are independently selected at each occurrence from 1-4;

n is independently selected at each occurrence from 0-2;

p, q, and z are independently selected at each occurrence from 0-3;

t and w are independently selected at each occurrence from 1-6,

provided that when J is CX′ and K and L are both CH, and M is CR⁵, then

(A) when V and Y are N and Z is CH and R¹ and R³ are methyl,

(1) and R⁴ is methyl, then

(a) R⁵ can not be methyl when X is OH and X′ is H;

(b) R⁵ can not be —NHCH₃ or —N(CH₃)₂ when X and X′ are —OCH₃; and

(c) R⁵ can not be —N(CH₃)₂ when X and X′ are —OCH₂CH₃;

(2) and R⁴ is ethyl, then

(a) then R⁵ can not be methylamine when X and X′are —OCH₃;

(b) R⁵ can not be OH when X is Br and X′ is OH; and

(c) R⁵ can not be —CH₂OH or —CH₂N(CH₃)₂ when X is —SCH3 and X′ is H;

(B) when V and Y are N, Z is CH, R⁴ is ethyl, R⁵ is iso-propyl, X is Br,X′ is H, and

(1) R¹ is CH₃, then

(a) R³ can not be OH, piperazin-1-yl, —CH₂-piperidin-1-yl,—CH₂—(N-4-methylpiperazin-1-yl), —C(O)NH-phenyl, —CO₂H,—CH₂O-(4-pyridyl), —C(O)NH₂, 2-indolyl, —CH₂O-(4-carboxyphenyl),—N(CH₂CH₃)(2-bromo-4-isopropylphenyl);

(2) R¹ is —CH₂CH₂CH₃ then R³ can not be —CH₂CH₂CH₃;

(C) when V, Y and Z are N, R⁴ is ethyl, and

(1) R⁵ is iso-propyl, X is bromo, and X′ is H, then

(a) R³ can not be OH or —OCH₂CN when R¹ is CH₃; and

(b) R³ can not be —N(CH₃)₂ when R¹ is —N(CH₃)₂;

(2) R⁵ is —OCH—, X is —OCH₃, and X′ is H, then R³ and R¹ can not both bechloro;

further provided that when J, K, and L are all CH and M is CR⁵, then

(D) at least one of V, Y, and Z must be N;

(E) when V is CR^(1a), Z and Y can not both be N;

(F) when Y is CR^(3a), Z and V can not both be N;

(G) when Z is CR², V and Y must both be N;

(H) Z can be N only when both V and Y are N or when V is CR^(1a) and Yis CR^(3a);

(I) when V and Y are N, Z is CR², and R² is H or C₁-C₃ alkyl, and R⁴ isC₁-C₃ alkyl, R³ can not be 2-pyridinyl, indolyl, indolinyl, imidazolyl,3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, or 4-pyrazinyl;

(J) when V and Y are N; Z is CR²; R² is H or C₁-C₃ alkyl; R⁴ is C₁-C₄alkyl; R⁵, X, and/or X′ are OH, halo, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, amino, carbamoyl, or C₁-C₄ alkanoyl; and R¹ isC₁-C₄ alkyl, then R³ can not be —NH(substituted phenyl) or —N(C₁-C₄alkyl)(substituted phenyl);

and wherein, when Y is CR²⁹:

J, K, L, M, Z, A, k, m, n, p, q, r, t, w, R³, R¹⁰, R¹¹, R¹², R¹³, R¹⁶,R¹⁸, R¹⁹, R²¹, R²³, R²⁴, R²⁵, and R²⁷ are as defined above and R^(25a),in addition to being as defined above, can also be C₁-C₄ alkyl, but

V is N;

R¹ is C₁-C₂ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ alkoxy, halogen,amino, methylamino, dimethylamino, aminomethyl, or N-methylaminomethyl;

R² is independently selected at each occurrence from the groupconsisting of hydrogen, halo, C₁-C₃ alkyl, nitro, amino, and —CO₂R¹⁰;

R⁴ is taken together with R²⁹ to form a 5-membered ring and is —C(R²⁸)═or —N═ when R²⁹ is —C(R³⁰)═ or —N═, or —CH(R²⁸)— when R²⁹ is —CH(R³⁰)—;

X is Cl, Br, I, S(O)_(n)R⁸, OR⁸, halomethyl, —(CHR¹⁶)_(p)OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀)-alkyl, C₃-C₆ cycloalkyl,aryl-(C₁-C₁₀ )-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

X′ is hydrogen, Cl, Br, I, S(O)_(n)R⁸, —(CHR¹⁶)_(p)OR⁸, halomethyl,cyano, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀, alkoxy, aryl-(C₁-C₁₀)-alkyl, C₃-C₆ cycloalkyl,aryl-(C₂-C₁₀)-alkoxy, nitro, thio-(C₂-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or C(═O)NR⁸R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

R⁵ is halo, —C(═NOR¹⁶)—C₁-C₄-alkyl, C₁-C₆ alkyl, C1-C3 haloalkyl, C₁-C₆alkoxy, (CHR¹⁶)_(p)OR⁸, (CHR¹⁶)_(p)S(O)_(n)R⁸, (CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃-C₆cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl-(C₂-C₁₀)-alkyl,aryl-(C₁-C₁₀)-alkoxy, cyano, C₃-C₆ cycloalkoxy, nitro,amino-(C₁-C₁₀)-alkyl, thio-(C₁-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or C(═O)NR⁸R¹⁵ where substitution by R¹⁸ can occur on anycarbon containing substituents;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(k)R¹³,(C₄-C₁₂)-cycloalkylalkyl, C₁-C₆ alkoxy, —(C₁-C₆ alkyl)-aryl, heteroaryl,aryl, —S(O)_(z)-aryl or —(C₁-C₆ alkyl)-heteroaryl or aryl wherein thearyl or heteroaryl groups are optionally substituted with 1-3 groupsselected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, nitro, carboxy,CO₂(C₁-C₆ alkyl), and cyano; or can be taken together to form—(CH₂)_(q)A(CH₂)_(r)—, optionally substituted with 0-3 R¹⁷; or, whenconsidered with the commonly attached nitrogen, can be taken together toform a heterocycle, said heterocycle being substituted on carbon with1-3 groups consisting of hydrogen, C₁-C₆ alkyl, hydroxy, or C₁-C₆alkoxy;

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, —(C₄-C₁₂) cycloalkylalkyl,(CH₂)_(t)R²², C₃-C₁₀ cycloalkyl, —(C₁-C₆ alkyl)-aryl, heteroaryl, —NR¹⁶,—N(CH₂)_(n)NR⁶R⁷; —(CH₂)_(k)R²⁵, —(C₁-C₆ alkyl)-heteroaryl or aryloptionally substituted with 1-3 groups selected from hydrogen, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, nitro, carboxy, CO₂(C₁-C₆ alkyl), and cyano;

R⁹ is independently selected at each occurrence from R¹⁰, hydroxy, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, and aryl substituted with 0-3R¹⁸;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, (CH₂)_(t)R²², andaryl substituted with 0-3 R¹⁸;

R¹⁷ is independently selected at each occurrence from the groupconsisting of R¹⁰, C₁-C₄ alkoxy, halo, OR²³, SR²³, and NR²³R²⁴;

R²⁰ is independently selected at each occurrence from the groupconsisting of R¹⁰ and C(═O)R³¹;

R²² is independently selected at each occurrence from the groupconsisting of cyano, OR²⁴, SR²⁴, NR²³R²⁴, C₃-C₆ cycloalkyl,—S(O)_(n)R³¹, and —C(═O)R²⁵;

R²⁶ is hydrogen or halogen:

R²⁸ is C₁-C₂ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, hydrogen, C₁-C₂alkoxy, halogen, or C₂-C₄ alkylamino;

R²⁹ is taken together with R⁴ to form a five membered ring and is:—CH(R³⁰)— when R⁴ is —CH(R²⁸)—, —C(R³⁰)═ or —N═ when R⁴ is —C(R²⁸)═ or—N═;

R³⁰ is hydrogen, cyano, C₁-C₂ alkyl, C₁-C₂ alkoxy, halogen, C₁-C₂alkenyl, nitro, amido, carboxy, or amino;

R³¹ is C₁-C₄ alkyl, C₃-C₇ cycloalkyl, or aryl-(C₁-C₄) alkyl;

provided that when J, K, and L are all CH, M is CR⁵, Z is CH, R³ is CH₃,R²⁸ is H, R⁵ is iso-propyl, X is Br, X′ is H, and R¹ is CH₃, then R³⁰can not be H, —CO₂H, or —CH₂NH₂;

and further provided that when J, K and L are all CH; M is CR⁵; Z is N;and

(A) R²⁹ is —C(R¹)═; then one of R²⁸ or R³⁰ is hydrogen;

(B) R²⁹ is N; then R³ is not halo, NH₂, NO₂, CF₃, CO₂H, CO₂-alkyl,alkyl, acyl, alkoxy, OH, or —(CH₂)_(m)Oalkyl;

(C) R²⁹ is N; then R²⁸ is not methyl if X or X′ are bromo or methyl andR⁵ is nitro; or

(D) R²⁹ is N, and R¹ is CH₃ and R³ is amino; then R⁵ is not halogen ormethyl.

Preferred compounds of this invention are those compounds of Formula Iwherein,

Y is CR^(3a) or N:

R³ is C₁-C₄ alkyl, aryl, halogen, C₁-C₂ haloalkyl, nitro, NR⁶R⁷, OR⁸,SR⁸, C(═O)R⁹, C(═O)NR⁶R⁷, C(═S)NR⁶R⁷, (CH₂)_(k)NR⁶R⁷, (CH₂)_(k)OR⁸,C(═O)NR¹⁰CH(R¹¹)CO₂R¹², —(CHR¹⁶)_(p)OR⁸, —C(OH)(R²⁵)(R^(25a)),—(CH₂)_(p)S(O)_(n)-alkyl, —C(CN)(R²⁵)(R¹⁶) provided that R²⁵ is not an—NH— containing ring, —C(═O)R²⁵, —CH(CO₂R¹⁶)₂, NR¹⁰C(═O)CH(R¹¹)NR¹⁰R¹²;substituted C₁-C₄alkyl, substituted C₂-C₄ alkenyl, substituted C₂-C₄alkynyl, C₃-C₆ cycloalkyl, substituted C₁-C₄ alkoxy, aryl-(substitutedC₁-C₄) alkyl, aryl-(substituted C₁-C₄) alkoxy, substituted C₃-C₆cycloalkyl, amino-(substituted C₁-C₄)alkyl, substituted C₁-C₄alkylamino, where substitution by R²⁷ can occur on any carbon containingsubstituent; 2-pyridinyl, indolinyl, indolyl, pyrazoyl, imidazolyl,3-pyridinyl, 4-pyridinyl, furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, or 5-methyl-2-thienyl, azetidinyl, 2-pyrrolidonyl,2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl,azocinyl, azepinyl, benzofuranyl, benzothiophenyl, carbazolyl,chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl,imidazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl),isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiazolyl, triazinyl; or1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which canbe substituted with 0-3 groups chosen from keto and C₁-C₄ alkyl;

J, K, and L are independently selected at each occurrence from the groupconsisting of CH and CX′;

M is CR⁵;

R^(1a), R², and R^(3a) are independently selected at each occurrencefrom the group consisting of hydrogen, halo, methyl, or cyano;

X is halogen, S(O)₂R⁸, SR⁸ halomethyl, (CH₂)_(p)OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀)-alkyl, C₃-C₆ cycloalkyl,aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, -C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

X′ is hydrogen, halogen, S(O)_(n)R⁸, halomethyl, (CH₂)_(p)OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀-alkyl, C₃-C₆ cycloalkyl,aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl, —C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵ where substitution by R¹⁸can occur on any carbon containing substituents;

R⁵ is halo, —C(═NOR¹⁶)—C₁-C₄-alkyl, C₁-C₆ alkyl, C₁-C₃ haloalkyl, C₁-C₆alkoxy, (CHR¹⁶)_(p)OR⁸, (CHR¹⁶)_(p)S(O)_(n)R⁸, (CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃-C₆cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl-(C₂-C₁₀)-akyl,aryl-(C₂-C₁₀)-alkoxy, cyano, C₃-C₆ cycloalkoxy, nitro,amino-(C₂-C₁₀)-alkyl, thio-(C₂-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or C(═O)NR¹⁴R¹⁵ where substitution by R¹⁸ can occur on anycarbon containing substituents;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl,—(CH₂)_(k)R¹³, C₁-C₆ alkoxy, —(CHR¹⁶)_(p)OR⁸, —(C₁-C₆ alkyl)-aryl, aryl,heteroaryl, —(C₁-C₆ alkyl)-heteroaryl or aryl, wherein the aryl orheteroaryl groups are optionally substituted with 1-3 groups selectedfrom hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, NHC(═O)(C₁-C₆ alkyl),NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, carboxy, CO₂(C₁-C₆ alkyl), cyano, orcan be taken together to form —(CH₂)_(q)A(CH₂)_(r)—, optionallysubstituted with 0-3 R¹⁷, or, when considered with the commonly attachednitrogen, can be taken together to form a heterocycle, said heterocyclebeing substituted on carbon with 1-3 groups consisting of hydrogen,C₁-C₆ alkyl, (C₁-C₆)alkyl(C₁-C₄)alkoxy, and C₁-C₆ alkoxy;

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen; C₁-C₆ alkyl; —(C₄-C₁₂) cycloalkylalkyl;(CH₂)_(t)R²²; C₃-C₁₀ cycloalkyl; —NR⁶R⁷; aryl; —NR¹⁶(CH₂)_(n)NR⁶R⁷;—(CH₂)_(k)R²⁵; and CH₂)_(t)heteroaryl or (CH₂)_(t)aryl, either of whichcan optionally be substituted with 1-3 groups selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, carboxy, andCO₂(C₁-C₆ alkyl);

R¹⁰ is hydrogen;

R¹³ is independently selected at each occurrence from the groupconsisting of OR¹⁹, SR¹⁹, and C₃-C₆ cycloalkyl;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₄-C₁₀cycloalkyl-alkyl;

R¹⁷ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, and(C₁-C₆)alkyl(C₁-C₄)alkoxy;

R¹⁹ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and aryl substituted with0-3 R¹⁸;

R²² is independently selected at each occurrence from the groupconsisting of cyano, OR²⁴ SR²⁴, NR²³R²⁴, C₃-C₆ cycloalkyl, —S(O)_(n)R³¹,and —C(═O)R²⁵;

R²⁵, which can be optionally substituted with 0-3 R¹⁷, is independentlyselected at each occurrence from the group consisting of phenyl,pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl,1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl,4aH-carbazolyl, 4H-quinolizinyl, azocinyl, benzofuranyl, carbazolyl,chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl,indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl,pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl,triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyleither of which can be substituted with 0-3 groups chosen from keto andC₁-C₄ alkyl;

R^(25a), which can be optionally substituted with 0-3 R¹⁷, isindependently selected at each occurrence from the group consisting ofH, phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, azocinyl, benzofuranyl,benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, quinuclidinyl, β-carbolinyl,tetrahydrofuranyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl; and1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which canbe substituted with 0-3 groups chosen from keto and C₁-C₄ alkyl;

t is independently selected at each occurrence from 1-3; and

w is 1-3.

Other preferred compounds of this invention are those compounds ofFormula I wherein,

Y is CR²⁹;

Z is CR²;

R¹ is methyl, amino, chloro, or methylamino;

R² is hydrogen;

R³ is C₁-C₄ alkyl, aryl, halogen, nitro, NR⁶R⁷, OR⁸, SR⁸, C(═O)R⁹,C(═O)NR⁶R⁷, (CH₂)_(k)NR⁶R⁷, (CH₂)_(k)OR⁸, —C(OH)(R²⁵)(R^(25a)),—(CH₂)_(p)S(O)_(n)-alkyl, —C(═O)R²⁵, —CH(CO₂R¹⁶)₂; substitutedC₁-C₄alkyl, substituted C₂-C₄ alkenyl, substituted C₂-C₄ alkynyl, C₃-C₆cycloalkyl, substituted C₁-C₄ alkoxy, aryl-(substituted C₁-C₄) alkyl,aryl-(substituted C₁-C₄) alkoxy, substituted C₃-C₆ cycloalkyl,amino-(substituted C₁-C₄) alkyl, substituted C₁-C₄ alkylamino, or isN-linked piperidinyl, piperazinyl, morpholino, thiomorpholino,imidazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, where substitution byR²⁷ can occur on any carbon containing substituent;

J, K, and L are independently selected at each occurrence from the groupconsisting of CH and CX′;

M is CR⁵;

R⁴ is taken together with R²⁹ to form a five membered ring and is —CH═;

X is Br, I, S(O)_(n)R⁸, OR⁸, NR¹⁴R¹⁵, R¹⁸ substituted alkyl, oramino-(C₁-C₂) alkyl;

X′ is hydrogen, Br, I, S(O)_(n)R⁸, OR⁸, NR¹⁴R¹⁵, R¹⁸ substituted alkyl,or amino-(C₁-C₂) alkyl;

R⁵ is independently selected at each occurrence from the groupconsisting of halogen, -C(═NOR¹⁶)—C₁-C₄-alkyl, C₁-C₆ alkyl, C₁-C₆alkoxy, (CHR¹⁶)_(p)OR⁸, —NR¹⁴R¹⁵, (CHR¹⁶)_(p)S(O)_(n)R⁸,(CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃-C₆ cycloalkyl, C(═O)R⁸, and C(═O)NR⁸R¹⁵; R⁶ andR⁷ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, —(CH₂)_(k)R¹³,(C₃-C₆)cycloalkyl-(C₁-C₆)alkyl, —(C₁-C₆ alkyl)-aryl, heteroaryl, —(C₁-C₆alkyl)-heteroaryl or aryl, wherein the aryl or heteroaryl groups areoptionally substituted with 1-3 groups selected from hydrogen, C₁-C₂alkyl, C₁-C₂ alkoxy, amino, NHC(═O)(C₁-C₂ alkyl), NH(C₁-C₂alkyl), andN(C₁-C₂ alkyl)₂, or can be taken together to form —(CH₂)_(q)A(CH₂)_(r)—,optionally substituted with 0-2 R¹⁷, or, when considered with thecommonly attached nitrogen, can be taken together to form a heterocycle,said heterocycle being substituted on carbon with 1-2 groups consistingof hydrogen, C₁-C₃ alkyl, hydroxy, or C₁-C₃ alkoxy;

A is CH₂, O, NR²⁵, C(═O), or S(O)_(n);

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen; C₁-C₆ alkyl; —(C₄-C₁₂) cycloalkylalkyl;(CH₂)_(t)R²²; C₃-C₁₀ cycloalkyl; —NR⁶R⁷; aryl; —NR¹⁶(CH₂)_(n)NR⁶R⁷;—(CH₂)_(k)R²⁵; and (CH₂)_(t)heteroaryl or (CH₂)_(t)aryl, either of whichcan optionally be substituted with 1-3 groups selected from the groupconsisting of hydrogen, C₁-C₂ alkyl, C₁-C₂ alkoxy, amino,NHC(═O)(C₁-C₂alkyl), NH(C₁-C₂alkyl), N(C₁-C₂ alkyl),, R⁹ is hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, and C₃-C₆ cycloalkyl substituted with 0-2R¹⁸;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₂ alkyl, (CH₂)_(t)R²², and aryl substitutedwith 0-2 R¹⁸;

R¹⁶ is independently selected at each occurrence from the groupconsisting of hydrogen and C₁-C₂ alkyl;

R¹⁷ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₂ alkyl, C₁-C₂ alkoxy, halo, and NR²³R²⁴;

R¹⁸ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₂ alkyl, C₁-C₂alkoxy, halo, and NR²³R²⁴;

R²² is independently selected at each occurrence from the groupconsisting of OR²⁴, SR²⁴, R²³R²⁴, and —C(═O)R²⁵;

R²³ and R²⁴ are independently selected at each occurrence from hydrogenand C₁-C₂ alkyl;

R²⁵, which can be optionally substituted with 0-3 R¹⁷, is independentlyselected at each occurrence from the group consisting of phenyl,pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl,1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl,4aH-carbazolyl, 4H-quinolizinyl, azocinyl, benzofuranyl, carbazolyl,chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, furazanyl,indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,isoindolinyl, isoindolyl, isoquinolinyl, benzimidazolyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl,pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl,triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyleither of which can be substituted with 0-3 groups chosen from keto andC₁-C₄ alkyl;

R^(25a) is independently selected at each occurrence from the groupconsisting of H and C₁-C₄ alkyl;

R²⁹ is taken together with R⁴ to form a five membered ring and is—C(R³⁰)═;

R³⁰ is hydrogen, cyano, C₁-C₂ alkyl, or halogen;

k is 1-3;

p is 0-2;

q and r are 2; and

t and w are independently selected at each occurrence from 1-2.

More preferred compounds of this invention are those compounds ofFormula I wherein, when Y is CR^(3a) or N:

R¹ is independently selected at each occurrence from the groupconsisting of C₁-C₂ alkyl, C₁-C₂ haloalkyl, NR⁶R⁷, and OR⁸;

R³ is independently selected at each occurrence from the groupconsisting of C₁-C₄ alkyl, C₁-C₂ haloalkyl, NR⁶R⁷, OR⁸, C(═O)R⁹,C(═O)NR⁶R⁷, (CH₂)_(k)NR⁶R⁷, (CH₂)_(k)OR⁸, —C(CN)(R²⁵)(R¹⁶) provided thatR²⁵ is not an —NH— containing ring, —C(OH)(R²⁵)(R^(25a)),—(CH₂)_(p)S(O)_(n)-alkyl, —C(═O)R²⁵, —CH(CO₂R¹⁶)₂, 2-pyridinyl,indolinyl, indolyl, pyrazoyl, imidazolyl, 3-pyridinyl, 4-pyridinyl,furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,5-methyl-2-thienyl, 1H-indazolyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4H-quinolizinyl, benzofuranyl, carbazolyl, chromenyl,cinnolinyl, decahydroquinolinyl, furazanyl, imidazolidinyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isoindolinyl, isoindolyl,isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiazolyl, triazinyl; and1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which canbe substituted with 0-3 groups chosen from keto and C₁-C₄ alkyl;

R^(1a), R², and R^(3a) are independently selected at each occurrencefrom the group consisting of hydrogen, methyl, and cyano;

X is Cl, Br, I, OR⁸, NR¹⁴R¹⁵, (CH₂)_(m)OR¹⁶, or (CHR¹⁶)NR¹⁴R¹⁵;

X′ is hydrogen, Cl, Br, I, OR⁸, NR¹⁴R¹⁵, (CH₂)_(m)OR¹⁶, or(CHR¹⁶)NR¹⁴R¹⁵;

R⁵ is halo, C₁-C₆ alkyl, C₁-C₃ haloalkyl, C₁-C₆ alkoxy, (CHR¹⁶)_(p)OR⁸,(CHR¹⁶)_(p)NR¹⁴R¹⁵, or C₃-C₆ cycloalkyl;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of

C₁-C₆ alkyl, (CHR¹⁶)_(p)OR⁸, C₁-C₆ alkoxy, and —(CH₂)_(k)R¹³, or can betaken together to form —(CH₂)_(q)A(CH₂)_(r)—, optionally substitutedwith —CH₂OCH₃;

A is CH₂, O, S(O)_(n), N(C(═O)R¹⁷), N(R¹⁹), C(H)(OR²⁰), NR²⁵, or C(═O);

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, (CH₂)_(t)R²²,—NR⁶R⁷, —NR¹⁶(CH₂)_(n)NR⁶R⁷, and —(CH₂)_(k)R²⁵,

R⁹ is C₁-C₄ alkyl;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₂ alkyl, C₃-C₆ cycloalkyl, and C₄-C₆cycloalkyl-alkyl;

R¹⁶ is hydrogen;

R^(1a) is C₁-C₃ alkyl;

R²⁰ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₂ alkyl, and C₂-C₃ alkenyl;

R²² is independently selected at each occurrence from the groupconsisting of OR²⁴, —S(O)_(n)R¹⁹, and —C(═O)R²⁵;

R²³ and R²⁴ are independently selected at each occurrence from hydrogenand C₁-C₂ alkyl;

R²⁵, which can be optionally substituted with 0-3 R¹⁷, is independentlyselected at each occurrence from the group consisting of phenyl,pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl,1H-indazolyl, 2-pyrrolidonyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl,4aH-carbazolyl, 4H-quinolizinyl, azocinyl, cinnolinyl,decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pteridinyl, purinyl,pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl.quinuclidinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl, triazinyl; and1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of which canbe substituted with 0-3 groups chosen from keto and C₁-C₄ alkyl;

R^(25a), which can be optionally substituted with 0-3 R¹⁷, isindependently selected at each occurrence from the group consisting ofH, phenyl, pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl,4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,2-pheno-thiazinyl, 4-pyrazinyl, 1H-indazolyl, 2-pyrrolidonyl,2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, azocinyl, cinnolinyl,decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isoindolinyl, isoindolyl, isoquinolinyl,benzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, β-carbolinyl, tetrahydrofuranyl, tetrazolyl, thiazolyl,triazinyl; and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyleither of which can be substituted with 0-3 groups chosen from keto andC₁-C₄ alkyl;

k is 1-3;

p and q are 0-2; and

r is 1-2.

Other more preferred compounds of this invention are those compounds ofFormula I wherein, when Y is CR²⁹:

R¹ is methyl;

R³ is C₁-C₂ alkyl, NR⁶R⁷, OR⁸, SR⁸, C₁-C₂ alkyl or aryl substituted withR²⁷, halogen, or is N-linked piperidinyl, piperazinyl, morpholino,thiomorpholino, imidazolyl, or is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,where substitution by R²⁷ can occur on any carbon containingsubstituent;

X is Br, I, S(O)_(n)R⁸, OR⁸, NR¹⁴R¹⁵, or alkyl substituted with R⁵;

X′ is hydrogen, Br, I, S(O)_(n)R⁸, OR⁸, NR¹⁴R¹⁵, or alkyl substitutedwith R⁵;

R⁵ is halogen, C₁-C₂ alkyl, C₁-C₂ alkoxy, or —NR¹⁴R¹⁵;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of hydrogen and C₁-C₂ alkyl, or, when considered with thecommonly attached nitrogen, can be taken together to form piperidine,piperazine, morpholine or thiomorpholine;

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₂ alkyl, and aryl optionally substitutedwith 1-2 groups selected from hydrogen, C₁-C₂ alkyl, C₁-C₂ alkoxy,NHC(═O)(C₁-C₂ alkyl), NH(C₁-C₂alkyl), and N(C₁-C₂ alkyl)₂;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen and C₁-C₂ alkyl; and

R³⁰ is hydrogen or cyano.

The following compounds are specifically preferred:

N-(2,4-dimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-methylphenyl)-N-methyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-cyclohexylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;

N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-pyrimidinamine;

N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiomorpholino-6-methyl-2-pyrimidinamine;

N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrmidinamine;

N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-thiomorpholino-2-pyrimidinamine;

N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,4-diiodophenyl)-N-ethyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxyethylamino)-2-pyrimidinamine;

N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-iodophenyl)-N-methyl-4,6-diethyl-2-pyrmidinamine;

N-(2-iodophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;

4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-methylamino)pyridine;

4,6-dimethyl-2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethylamino)pyridine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;

2,6-dimethyl-4-(N-(2-bromo-4-(1-methylethyl)phenyl)amino)pyridine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylcarbonyl)-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(morpholinylmethyl)-2-pyrimidinamine;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbonyl)-2-pyrimidinamine;

Methyl-2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylate;

2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyrimidinecarboxamide;

N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazinylcarbonyl)-2-pyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-1,3,5-triazin-2-amine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

N-ethyl)-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(4-thiomorpholinyl)-1,3,5-triazin-2-amine;

N-ethyl-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine;

N-ethyl-N-{2-iodo-4-(1-methylethyl)phenyl}-4-methyl-6-(1-piperidinyl)-1,3,5-triazin-2-amine;

1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4-phenyl-6-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-phenyl-6-methyl-7-azaindole;

1-(2-bromo-4,6-dimethoxyphenyl)-1)-3-cyano-4,6-dimethyl-7-azaindole:

1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-N,N-diethylamino-6-methyl-1,3,5triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4,6-dichloro-1,3,5triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4,6-dimethoxy-1,3,5triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-imidazolino-6-methyl-1,3,5triazin-2-amine;

N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5triazin-2-amine;

N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-N,N-dimethylamino-6-methyl-1,3,5triazin-2-amine;

N-(2,4,6-trimethoxyphenyl)-N-ethyl-4-morpholino-6-methyl-1,3,5triazin-2-amine,

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-N,N-dimethylamino-6-methyl-1,3,5triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-thiozolidino-6-methyl-1,3,5triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-benzyloxy-6-methyl-1,3,5triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-phenyloxy-6-methyl-1,3,5triazin-2-amine;

N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-{4-(ethylpiperizinoate)}-6-methyl-1,3,5triazin-2-amine;

N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-{4-(piperizinicacid)}-6-methyl-1,3,5 triazin-2-amine;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-{3-(malon-2-yldiethylester)}-6-methyl-1,3,5-triazin-2-amine;

N-(2-bromo-4,6-dimethoxyphenyl)-N-ethyl-4-(1-cyano-1-phenylmethyl)-6-methyl-1,3,5triazin-2-amine;

N-(2-bromo-4,6-dimethoxyphenyl)-N-1-methylethyl-4-morpholino-6-methyl-1,3,5triazin-2-amine;

N-(2-iodo-4-dimethylhydroxymethylphenyl)-N-ethyl-4,6-dichloro-1,3,5triazin-2-amine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine,S-dioxide;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine,S-oxide;

N-{2-bromo-4(1-methylethyl)phenyl}-N-ethyl-4-methyl-6-benzyloxy-1,3,5triazin-2-amine;

N-(2-iodo-4-dimethylhydroxymethyl)-N-ethyl-4,6-dichloro-1,3,5triazin-2-amine;

N-{2-iodo-4-(1-methylethyl)phenyl}-N-allyl-4-morpholino-6-methyl-2-pyrimidinamine;

N-{2-iodo-4-(1-methylethyl)phenyl}-N-ethyl-4-chloro-6-methyl-2-pyrimidinamine;

N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4(S)-(N-methyl-2-pyrrolidinomethoxy)-6-methyl-2-pyrimidinamine;

N-{2,6-dibromo-4-(1-methylethyl)phenyl}-4-thiomorpholino-6-methyl-2-pyrimidinamine;

N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{2-methylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{2-methylsulfinyl-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{2-iodo-4-(1-methylethyl)phenyl}-N-ethyl-4-thiazolidino-6-methyl-2-pyrimidinamine;

N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4,6-dimethyl-2-pyrimidinamino)-2,3,4,5-tetrahydro-4-(1-methylethyl)-1,5-benzothiazepine;

N-{2-methylsulfonyl-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{2-ethylthio-4-(1-methylethyl)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinamine;

N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{2-methylthio-4-(N-acetyl-N-methylamino)phenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyirmidinamine;

N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{4-(1-methoxyethyl)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{4-(N-methylamino)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{4-(N,N-dimethylamino)-2-methylthiophenyl}-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-formyl-6-methyl-2-pyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-hydroxyethoxymethyl-6-methyl-2-pyrimidinamine;

N-(2-bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(3-bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,3-dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2,6-dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole;

1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole;

1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano4-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-chloro-34yano-methyl-7-azaindole;

1-(2-bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole;

N-(2-bromo-6-methoxy-pyridin-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(3-bromo-5-methyl-pyridin-2-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(6-methoxy-pyridin-3-yl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;

N-(2-bromo-6-methoxy-pyridin-3-yl)-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5triazin-2-amine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{N-(2-furylmethyl)-N-methylamino}carbonyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{(4,4-ethylenedioxypiperidino)carbonyl}-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-oxopiperidino)carbonyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-oxopiperidino)methyl-6-methylpyrimidinamine,hydrochloride salt;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{3-(methoxyphenyl)methoxymethyl}-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(5-indolylcarbonyl)-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(4-fluorophenyl)carbonyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-carboxy-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-acetyl-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{4-(methoxyphenyl)-3-pyridyl-hydroxymethyl}-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimidinamine,hydrochloride salt;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(1-aminoethyl)-6-methylpyrimidinamine;

N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-{2-(4-tetrazolyl)-1-methylethyl}-6-methylpyrimidinamine;

2-(N-{2-bromo-4-(2-propyl)phenyl}amino)-4-carbomethoxy-6-methylpyrimidine;

2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-4-carbomethoxy-6-methylpyrimidine;

2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-6-methylpyrimidine-4-morpholinocarbonyl;

9{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino purine;

9{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino-8-azapurine;

1{2-bromo-4-(2-propyl)phenyl}-2-methyl-6-morpholino-5,7-diaza-indazole;and

2-(N-{2-bromo-4-(2-propyl)phenyl}-N-ethylamino)-4-(morpholinomethyl)-6-methylpyrimidine.

The above-described compounds and their corresponding salts possessantagonistic activity for the corticotropin releasing factor receptorand can be used for treating affective disorders, anxiety, depression,irritable bowel syndrome, immune suppression, Alzheimer's disease,gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawalsymptoms, drug addiction, inflammatory disorders, or fertility problemsin mammals.

Further included in this invention is a method of treating affectivedisorders, anxiety, depression, irritable bowel syndrome, immunesuppression, Alzheimer's disease, gastrointestinal diseases, anorexianervosa, drug and alcohol withdrawal symptoms, drug addiction,inflammatory disorders, or fertility problems in mammals in need of suchtreatment comprising administering to the mammal a therapeuticallyeffective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein Y isCR^(3a),

N, or CR²⁹;

when Y is CR^(3a) or N:

R¹ is independently selected at each occurrence from the groupconsisting of C₁-C₄ alkyl, halogen, C₁-C₂ haloalkyl, NR⁶R⁷, OR⁸, andS(O)_(n)R⁸;

R³ is C₁-C₄ alkyl, aryl, C₃-C₆ cycloalkyl, C₁-C₂ haloalkyl, halogen,nitro, NR⁶R⁷, OR⁸, S(O)_(n)R⁸, C(═O)R⁹, C(═O)NR⁶R⁷, C(═S)NR⁶R⁷,—(CHR¹⁶)_(k)NR⁶R⁷, (CH₂)_(k)OR⁸, C(═O)NR¹⁰CH(R¹¹)CO₂R¹²,—C(OH)(R²⁵)(R^(25a)), —(CH₂)_(p)S(O)_(n)-alkyl, —(CHR¹⁶)R²⁵,—C(CN)(R²⁵)(R¹⁶) provided that R²⁵ is not —NH— containing rings,—C(═O)R²⁵, —CH(CO₂R¹⁶)₂, NR¹⁰C(═O)CH(R¹¹)NR¹⁰R¹², NR¹⁰CH(R¹¹)CO₂R¹²;substituted C₁-C₄ alkyl, substituted C₂-C₄ alkenyl, substituted C₂-C₄alkynyl, substituted C₁-C₄ alkoxy, aryl-(substituted C₁-C₄) alkyl,aryl-(substituted C₁-C₄) alkoxy, substituted C₃-C₆ cycloalkyl,amino-(substituted C₁-C₄) alkyl, substituted C₁-C₄ alkylamino, wheresubstitution by R²⁷ can occur on any carbon containing substituent;2-pyridinyl, imidazolyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl,4-methyl-3-pyridinyl, furanyl, 5-methyl-2-furanyl,2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,2-pheno-thiazinyl, 4-pyrazinyl, azetidinyl, phenyl, 1H-indazolyl,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, azepinyl, benzofuranyl, benzothiophenyl,carbazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,furazanyl, imidazolidinyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinylbenzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thianthrenyl, thiazolyl, thiophenyl,triazinyl, xanthenyl; or 1-tetrahydroquinolinyl or2-tetrahydroisoquinolinyl either of which can be substituted with 0-3groups chosen from keto and C₁-C₄ alkyl;

J, K, and L are independently selected at each occurrence from the groupof

N, CH, and CX′;

M is CR⁵ or N;

V is CR^(1a) or N;

Z is CR² or N;

R^(1a), R², and R^(3a) are independently selected at each occurrencefrom the group consisting of hydrogen, halo, halomethyl, C₁-C₃ alkyl,and cyano;

R⁴ is (CH₂)_(m)OR¹⁶, C₁-C₄ alkyl, allyl, propargyl, (CH₂)_(m)R¹³, or—(CH₂)_(m)OC(O)R¹⁶;

X is halogen, S(O)₂R⁸, SR⁸, halomethyl, —(CH₂)_(p)OR⁸, —OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, —C(═O)R⁸, C₁-C₆ alkyl, C₄-C₁₀ cycloalkylalkyl,C₁-C₁₀alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀alkoxy, aryl-(C₂-C₁₀)-alkyl, C₃-C₆cycloalkyl, aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

X′ is independently selected at each occurrence from the groupconsisting of hydrogen, halogen, S(O)_(n)R⁸, halomethyl,—(CHR¹⁶)_(p)OR⁸, cyano, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀)-alkyl,C₃-C₆ cycloalkyl, aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, and —C(═O)NR¹⁴R¹⁵ wheresubstitution by R¹⁸ can occur on any carbon containing substituents;

R⁵ is halo, —C(═NOR¹⁶)—C₁-₄-alkyl, C₁-C₆ alkyl, C₁-C₃ haloalkyl,—(CHR¹⁶)_(p)OR⁸, —(CHR¹⁶)_(p)S(O)_(n)R⁸, —(CHR¹⁶)_(p)NR¹⁴R¹⁵,C₃-C₆cycloalkyl, C₂-C₁₀alkenyl, C₁-C₁₀ alkynyl, aryl-(C₂-C₁₀)-akyl,aryl-(C₁-C₁₀)-alkoxy, cyano, C₃-C₆ cycloalkoxy, nitro,amino-(C₂-C₁₀)-alkyl, thio-(C₂-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵, where substitution by R¹⁸ can occur onany carbon containing substituents;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy,(C₄-C₁₂)-cycloalkylalkyl, —(CH₂)_(k)R¹³, (CHR¹⁶)_(p)OR⁸, —(C₁-C₆alkyl)-aryl, heteroaryl, aryl, —S(O)_(n)-aryl or —(C₁-C₆alkyl)-heteroaryl or aryl wherein the aryl or heteroaryl groups areoptionally substituted with 1-3 groups selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, nitro, carboxy,CO₂(C₁-C₆ alkyl), cyano, and S(O)_(z)—(C₁-C₆-alkyl); or can be takentogether to form —(CH₂)_(q)A(CH₂)_(r)—, optionally substituted with 0-3R¹⁷; or, when considered with the commonly attached nitrogen, can betaken together to form a heterocycle, said heterocycle being substitutedon carbon with 1-3 groups consisting of hydrogen, C₁-C₆ alkyl, hydroxy,or C₁-C₆ alkoxy;

A is CH₂, O, NR²⁵, C(═O), S(O)_(n), N(C(═O)R¹⁷), N(R¹⁹), C(H)(NR¹⁴R¹⁵),C(H)(OR²⁰), C(H)(C(═O)R²¹), or N(S(O)_(n)R²¹);

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen; C₁-C₆ alkyl; —(C₄-C₁₂) cycloalkylalkyl;(CH₂)_(n)R²²; C₃-C₁₀ cycloalkyl; —NR⁶R⁷; aryl; —NR¹⁶(CH₂)_(n)NR⁶R⁷;—(CH₂)_(k)R²⁵; and (CH₂)_(t)heteroaryl or (CH₂)_(t)aryl, either of whichcan optionally be substituted with 1-3 groups selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, nitro, carboxy,CO₂(C₁-C₆ alkyl), cyano, and S(O)_(z)(C₁-C₆-alkyl);

R⁹ is independently selected at each occurrence from R¹⁰, hydroxy, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, C₁-C₄ alkenyl, aryl substituted with 0-3 R¹⁸,and —(C₁-C₆ alkyl)-aryl substituted with 0-3 R¹⁸;

R¹⁰, R¹⁶, R²³, and R²⁴ are independently selected at each occurrencefrom hydrogen or C₁-C₄ alkyl;

R¹¹ is C₁-C₄ alkyl substituted with 0-3 groups chosen from thefollowing: keto, amino, sulfhydryl, hydroxyl, guanidinyl,p-hydroxyphenyl, imidazolyl, phenyl, indolyl, indolinyl, or, when takentogether with an adjacent R¹⁰, are (CH₂)_(t);

R₁₂ is hydrogen or an appropriate amine protecting group for nitrogen oran appropriate carboxylic acid protecting group for carboxyl;

R¹³ is independently selected at each occurrence from the groupconsisting of CN, OR¹⁹, SR¹⁹, and C₃-C₆ cycloalkyl;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₄-C₁₀ cycloalkyl-alkyl, and R¹⁹;

R¹⁷ is independently selected at each occurrence from the groupconsisting of R¹⁰, C₁-C₄ alkoxy, halo, OR²³, SR²³, NR²³R²⁴, and (C₁-C₆)alkyl (C₁-C₄) alkoxy;

R¹⁸ is independently selected at each occurrence from the groupconsisting of R¹⁰, hydroxy, halogen, C₁-C₂ haloalkyl, C₁-C₄ alkoxy,C(═O)R²⁴, and cyano;

R¹⁹ is independently selected at each occurrence from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, (CH₂)_(w)R²², and arylsubstituted with 0-3 R¹⁸;

R²⁰ is independently selected at each occurrence from the groupconsisting of R¹⁰, C(═O)R³¹, and C₂-C₄ alkenyl;

R²¹ is independently selected at each occurrence from the groupconsisting of R¹⁰, C₁-C₄ ⁻ alkoxy, NR²³R²⁴, and hydroxyl;

R²² is independently selected at each occurrence from the groupconsisting of cyano, OR²⁴, SR²⁴, NR²³R²⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,—S(O)_(n)R³¹, and —C(═O)R²⁵;

R²⁵, which can be optionally substituted with 0-3 R¹⁷, is independentlyselected at each occurrence from the group consisting of phenyl,pyrazolyl, imidazolyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl,azetidinyl, 1H-indazolyl, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazolyl, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, azepinyl, benzofuranyl,benzothiophenyl, carbazolyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, furazanyl, indolinyl, indolizinyl, indolyl,isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinylbenzimidazolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxazolidinyl, oxazolyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazolidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, quinuclidinyl, β-carbolinyl, tetrahydrofuranyl,tetrazolyl, thianthrenyl, thiazolyl, thiophenyl, triazinyl, xanthenyl;and 1-tetrahydroquinolinyl or 2-tetrahydroisoquinolinyl either of whichcan be substituted with 0-3 groups chosen from keto and C₁-C₄ alkyl;

R^(25a), which can be optionally substituted with 0-3 R¹⁷, isindependently selected at each occurrence from the group consisting of Hand R²⁵;

R²⁷ is independently selected at each occurrence from the groupconsisting of C₁-C₃ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ alkoxy,aryl, nitro, cyano, halogen, aryloxy, and heterocycle optionally linkedthrough O;

R³¹ is independently selected at each occurrence from the groupconsisting of C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₄-C₁₀ cycloalkyl-alkyl,and aryl-(C₁-C₄) alkyl;

k, m, and r are independently selected at each occurrence from 1-4;

n is independently selected at each occurrence from 0-2;

p, q, and z are independently selected at each occurrence from 0-3;

t and w are independently selected at each occurrence from 1-6,

provided that when J is CX′ and K and L are both CH, and M is CR⁵, then

(A) when V and Y are N and Z is CH and R¹ and R³ are methyl,

(1) and R⁴ is methyl, then

(a) R⁵ can not be methyl when X is OH and X′ is H;

(b) R⁵ can not be —NHCH₃ or —N(CH₃)₂ when X and X′ are —OCH₃; and

(c) R⁵ can not be -N(CH₃)₂ when X and X′ are —OCH₂CH₃;

(2) and R⁴ is ethyl, then

(a) then R⁵ can not be methylamine when X and X′ are —OCH₃;

(b) R⁵ can not be OH when X is Br and X′ is OH; and

(c) R⁵ can not be —CH₂OH or —CH₂N(CH₃)₂ when X is —SCH3 and X′ is H;

(B) when V and Y are N, Z is CH, R⁴ is ethyl, R⁵ is iso-propyl, X is Br,X′ is H, and

(1) R¹ is CH₃, then

(a) R³ can not be OH, piperazin-1-yl, —CH₂-piperidin-1-yl,—CH₂-(N-4-methylpiperazin- 1-yl), —C(O)NH-phenyl, —CO₂H,—CH₂O-(4-pyridyl), —C(O)NH₂, 2-indolyl, —CH₂O-(4-carboxyphenyl),—N(CH₂CH₃)(2-bromo-4-isopropylphenyl);

(2) R¹ is —CH₂CH₂CH₃ then R³ can not be —CH₂CH₂CH₃;

(C) when V, Y and Z are N, R⁴ is ethyl, and

(1) R⁵ is iso-propyl, X is bromo, and X′ is H, then

(a) R³ can not be OH or —OCH₂CN when R¹ is CH₃; and

(b) R³ can not be —N(CH₃)₂ when R¹ is —N(CH₃)₂;

(2) R⁵ is —OCH—, X is —OCH₃, and X′ is H, then R³ and R¹ can not both bechloro;

further provided that when J, K, and L are all CH and M is CR⁵, then

(D) at least one of V, Y, and Z must be N;

(E) when V is CR^(1a), Z and Y can not both be N;

(F) when Y is CR^(3a), Z and V can not both be N;

(G) when Z is CR², V and Y must both be N;

(H) Z can be N only when both V and Y are N or when V is CR^(1a) and Yis CR^(3a);

(I) when V and Y are N, Z is CR², and R² is H or C₁-C₃ alkyl, and R⁴ isC₁-C₃ alkyl, R³ can not be 2-pyridinyl, indolyl, indolinyl, imidazolyl,3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl,furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl,3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, or 4-pyrazinyl;

(J) when V and Y are N; Z is CR²; R² is H or C₁-C₃ alkyl; R⁴ is C₁-C₄alkyl; R⁵, X, and/or X′ are OH, halo, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, amino, carbamoyl, or C₁-C₄ alkanoyl; and R¹ isC₁-C₄ alkyl, then R³ can not be —NH(substituted phenyl) or —N(C₁-C₄alkyl)(substituted phenyl);

and wherein, when Y is CR²⁹:

J, K, L, M, Z, A, k, m, n, p, q, r, t, w, R³, R¹⁰, R¹¹, R¹², R¹³, R¹⁶,R¹⁸, R¹⁹, R²¹, R²³, R²⁴, R²⁵, and R²⁷ are as defined above and R^(25a),in addition to being as defined above, can also be C₁-C₄ alkyl, but

V is N;

R¹ is C₁-C₂ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₂-C₄ alkoxy, halogen,amino, methylamino, dimethylamino, aminomethyl, or N-methylaminomethyl;

R² is independently selected at each occurrence from the groupconsisting of hydrogen, halo, C₁-C₃ alkyl, nitro, amino, and —CO₂R¹⁰;

R⁴ is taken together with R²⁹ to form a 5-membered ring and is —C(R²⁸)═or —N═ when R²⁹ is —C(R³⁰)═ or —N═, or —CH(R²⁸)— when R²⁹ is

X is Cl, Br, I, S(O)_(n)R⁸, OR⁸, halomethyl, —(CHR¹⁶)_(p)OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀)-alkyl, C₃-C₆ cycloalkyl,aryl-(C₁-C₁₀ )-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, -C(═NOR¹⁶)H, or C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

X′ is hydrogen, Cl, Br, I, S(O)_(n)R⁸, —(CHR¹⁶)_(p)OR⁸, halomethyl,cyano, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀, alkoxy, aryl-(C₁-C₁₀)-alkyl, C₃-C₆ cycloalkyl,aryl-(C₂-C₁₀)-alkoxy, nitro, thio-(C₂-C₁₀)-alkyl,—C(═NOR¹⁶)-C₁-C₄-alkyl, —C(═NOR¹⁶)H, or C(═O)NR⁸R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents;

R⁵ is halo, —C(═NOR¹⁶)-C₁-C₄-alkyl, C₁-C₆ alkyl, C1-C3 haloalkyl, C₁-C₆alkoxy, (CHR¹⁶)_(p)OR⁸, (CHR¹⁶)_(p)S(O)_(n)R⁸, (CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃-C₆cycloalkyl, C₁-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl-(C₂-C₁₀)-alkyl,aryl-(C₁-C₁₀)-alkoxy, cyano, C₃-C₆ cycloalkoxy, nitro,amino-(C₁-C₁₀)-alkyl, thio-(C₁-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or C(═O)NR⁸R¹⁵ where substitution by R¹⁸ can occur on anycarbon containing substituents;

R⁶ and R⁷ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(k)R¹³,(C₄-C₁₂)-cycloalkylalkyl, C₁-C₆ alkoxy, —(C₁-C₆ alkyl)-aryl, heteroaryl,aryl, —S(O)_(z)-aryl or —(C₁-C₆ alkyl)-heteroaryl or aryl wherein thearyl or heteroaryl groups are optionally substituted with 1-3 groupsselected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl), nitro, carboxy,CO₂(C₁-C₆ alkyl), and cyano; or can be taken together to form—(CH₂)_(q)A(CH₂)_(r)—, optionally substituted with 0-3 R¹⁷; or, whenconsidered with the commonly attached nitrogen, can be taken together toform a heterocycle, said heterocycle being substituted on carbon with1-3 groups consisting of hydrogen, C₁-C₆ alkyl, hydroxy, or C₁-C₆alkoxy;

R⁸ is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, —(C₄-C₁₂) cycloalkylalkyl,(CH₂)_(t)R²², C₃-C₁₀ cycloalkyl, —(C₁-C₆ alkyl)-aryl, heteroaryl, —NR¹⁶,—N(CH₂)_(n)NR⁶R⁷; —(CH₂)_(k)R²⁵, —(C₁-C₆ alkyl)-heteroaryl or aryloptionally substituted with 1-3 groups selected from hydrogen, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)₂, nitro, carboxy, CO₂(C₁-C₆ alkyl), and cyano;

R⁹ is independently selected at each occurrence from R₂, hydroxy, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, and aryl substituted with 0-3R¹⁸;

R¹⁴ and R¹⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, (CH₂)_(t)R²², andaryl substituted with 0-3 R¹⁸;

R¹⁷ is independently selected at each occurrence from the groupconsisting of R¹⁰, C₁-C₄ alkoxy, halo, OR²³, SR²³, and NR²³R²⁴;

R²⁰ is independently selected at each occurrence from the groupconsisting of R¹⁰ and C(═O)R³¹;

R²² is independently selected at each occurrence from the groupconsisting of cyano, R²⁴, SR²⁴, NR²³R²⁴, C₃-C₆ cycloalkyl, —S(O)_(n)R³¹,and —C(═O)R²⁵;

R²⁶ is hydrogen or halogen:

R²⁸ is C₁-C₂ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, hydrogen, C₁-C₂alkoxy, halogen, or C₂-C₄ alkylamino; R²⁹ is taken together with R⁴ toform a five membered ring and is: —CH(R³⁰)— when R⁴ is —CH(R²⁸)—,—C(R³⁰)═ or —N═ when R⁴ is —C(R²⁸)═ or —N═;

R³⁰ is hydrogen, cyano, C₁-C₂ alkyl, C₁-C₂ alkoxy, halogen, C₁-C₂alkenyl, nitro, amido, carboxy, or amino;

R³¹ is C₁-C₄ alkyl, C₃-C₇ cycloalkyl, or aryl-(C₁-C₄) alkyl;

provided that when J, K, and L are all CH, M is CR⁵, Z is CH, R³ is CH₃,

R²⁸ is H, R⁵ is iso-propyl, X is Br, X′ is H, and R¹ is CH₃, then R³⁰can not be H, —CO₂H, or —CH₂NH₂;

and further provided that when J, K and L are all CH; M is CR⁵; Z is N;and

(A) R²⁹ is —C(R¹)═; then one of R²⁸ or R³⁰ is hydrogen;

(B) R²⁹ is N; then R³ is not halo, NH₂, NO₂, CF₃, CO₂H, CO₂-alkyl,alkyl, acyl, alkoxy, OH, or —(CH₂)_(m)Oalkyl;

(C) R²⁹ is N; then R²⁸ is not methyl if X or X′ are bromo or methyl andR⁵ is nitro; or

(D) R²⁹ is N, and R¹ is CH₃ and R³ is amino; then R⁵ is not halogen ormethyl.

Further included in this invention are pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and therapeuticallyeffective amount of any one of the above-described compounds.

The compounds provided by this invention (and especially labelledcompounds of this invention) are also useful as standards and reagentsin determining the ability of a potential pharmaceutical to bind to theCRF receptor. These would be provided in commercial kits comprising acompound provided by this invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention it has been discovered that the providedcompounds useful as antagonists of Cortocotropin Releasing Factor andfor the treatment of effective disorders, anxiety, or depression.

The present invention also provides methods for the treatment ofeffective disorder, anxiety or depression by administering to a host atherapeutically effective amount of a compound of formula (I) asdescribed above. By therapeutically effective amount is meant an amountof a compound of the present invention effective to antagonize abnormallevels of CRF or treat the symptoms of affective disorder, anxiety ordepression in a host.

The compounds herein described may have asymmetric centers. All chiral,diastereomeric, and racemic forms are included in the present invention.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compound described herein, and all such stableisomers are comtemplated in the present invention. It will beappreciated that certain compounds of the present invention contain anasymmetrically substituted carbon atom, and may be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis, from optically active starting materials. Also, it isrealized that cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomers forms. All chiral, diastereomeric, andracemic forms and all geometric isomers forms of a structure areintended, unless the specific stereochemistry or isomer form isspecifically indicated.

When any variable (for example, R¹ through R¹⁰, m, n, A, w, Z, etc.)occurs more than one time in any constituent or in formula (I) or anyother formula herein, its definition on each occurrence is independentof its definition at every other occurrence. Thus, for example, in—NR⁸R⁹, each of the substituents may be independently selected from thelist of possible R⁸ and R⁹ groups defined. Also, combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur at anystable point along the chain, such as ethenyl, propenyl, and the like.“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more triple carbon-carbon bondswhich may occur at any stable point along the chain, such as ethynyl,propynyl and the like. “Haloalkyl” is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogens;“alkoxy” represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge; “cycloalkyl” is intended to includesaturated ring groups, including mono-, bi- or poly-cyclic ring systems,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth.“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo.

As used herein, “aryl” or “aromatic residue” is intended to mean phenyl,biphenyl or naphthyl.

The term “heteroaryl” is meant to include unsubstituted, monosubstitutedor disubstituted 5-, 6- or 10-membered mono- or bicyclic aromatic rings,which can optionally contain from 1 to 3 heteroatoms selected from thegroup consisting of O, N, and S and are expected to be active. Includedin the definition of the group heteroaryl, but not limited thereto, arethe following: 2-, or 3-, or 4-pyridyl; 2- or 3-furyl; 2- or3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1-or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2- or 4-or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4- or 5-thiazolyl;2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3-or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl;2-pyrazinyl; 2-triazinyl; 3- or 4- cinnolinyl; 1-phthalazinyl; 2- or4-quinazolinyl; or 2-quinoxalinyl ring. Particularly preferred are 2-,3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen may optionally be quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom which results in a stable structure.The heterocyclic rings described herein may be substituted on carbon oron a nitrogen atom if the resulting compound is stable. Examples of suchheterocycles include, but are not limited to, pyridyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl,pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl oroctahydroisoquinolinyl, azocinyl, triazinyl, 6H- 1,2,5-thiadiazinyl,2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, furanyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl,pyrrole, imidazolyl, pyrazolyl, isothiazolyl, isoxazole, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindole, 3H-indolyl,indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl,quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl,quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ringand spiro compounds containing, for example, the above heterocycles.

The term “substituted”, as used herein, means that one or more hydrogensof the designated moiety is replaced with a selection from the indicatedgroup, provided that no atom's normal valency is exceeded, and that thesubstitution results in a stable compound. When a substituent is keto(i.e., ═O), then 2 hydrogens attached to an atom of the moiety arereplaced.

By “stable compound” or “stable structure” is meant herein a compoundthat is sufficiently robust to survive isolation to a useful degree ofpurity from a reaction mixture and formulation into an efficacioustherapeutic agent.

As used herein, the term “appropriate amino acid protecting group” meansany group known in the art of organic synthesis for the protection ofamine or carboxylic acid groups. Such amine protecting groups includethose listed in Greene and Wuts, “Protective Groups in OrganicSynthesis” John Wiley & Sons, New York (1991) and “The Peptides:Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981),the disclosure of which is hereby incorporated by reference. Any amineprotecting group known in the art can be used. Examples of amineprotecting groups include, but are not limited to, the following: 1)acyl types such as formyl, trifluoroacetyl, phthalyl, andp-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl(Cbz) and substituted benzyloxycarbonyls,1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl(Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl(Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl;4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl andadamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl;6) trialkylsilane such as trimethylsilane; and 7) thiol containing typessuch as phenylthiocarbonyl and dithiasuccinoyl.

The term “amino acid” as used herein means an organic compoundcontaining both a basic amino group and an acidic carboxyl group.Included within this term are natural amino acids, modified and unusualamino acids, as well as amino acids that are known to occur biologicallyin free or combined form but usually do not occur in proteins. Includedwithin this term are modified and unusual amino acids, such as, thosedisclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5:342-429, the teaching of which is hereby incorporated by reference.Modified or unusual amino acids that can be used in the practice of theinvention include, but are not limited to, D-amino acids, hydroxylysine,4-hydroxyproline, an N-Cbz-protected amino acid, ornithine,2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyricacid, naphthylalanine, phenylglycine, β-phenylproline, tert-leucine,4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline,N,N-dimethylaminoglycine, N-methylaminoglycine,4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid,trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid,1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.

The term “amino acid residue” as used herein means that portion of anamino acid (as defined herein) that is present in a peptide.

The term “peptide” as used herein means a compound that consists of twoor more amino acids (as defined herein) that are linked by means of apeptide bond. The term “peptide” also includes compounds containing bothpeptide and non-peptide components, such as pseudopeptide or peptidemimetic residues or other non-amino acid components. Such a compoundcontaining both peptide and non-peptide components may also be referredto as a “peptide analog”.

The term “peptide bond” means a covalent amide linkage formed by loss ofa molecule of water between the carboxyl group of one amino acid and theamino group of a second amino acid.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound of formula (I) ismodified by making acid or base salts of the compound of formula (I).Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

“Prodrugs” are considered to be any covalently bonded carriers thatrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of thecompounds of formula (I) are prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of formula (I) wherein hydroxy,amine, or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate and benzoate derivatives ofalcohol and amine functional groups in the compounds of formula (I); andthe like.

Pharmaceutically acceptable salts of the compounds of the invention canbe prepared by reacting the free acid or base forms of these compoundswith a stoichiometric amount of the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.(1985), p. 1418, the disclosure of which is hereby incorporated byreference.

SYNTHESIS

The novel substituted-2-pyridinamines, substituted triazines,substituted pyridines and substituted anilines of the present inventioncan be prepared by one of the general schemes outlined below (Scheme1-23).

Compounds of the Formula (I), wherein Z is CR² and J is CX′ and K and Lare both CH, can be prepared as shown in Scheme 1.2-Hydroxy-4,6-dialkylpyrimidine (II) was converted to the correspondingderivative (III) with an appropriate leaving group in the 2-positionsuch as, but not limited to, Cl, Br, SO₂CH₃, OSO₂CH₃, or OSO₂C₆H₄—CH₃,or SCH₃ by treatment with phosphorous oxychloride (POCl₃), phosphorousoxybromide (POBr₃), methanesulfonyl chloride (MsCl), p-toluenesulfonylchloride (TsCl), or sodium thiomethoxide optionally followed byoxidation with hydrogen peroxide, chlorine gas, or an organic peracid,such as, m-chloroperbenzoic

acid, respectively. This derivative was reacted with the appropriate2,4-substituted aniline (IV) in a high boiling solvent, such as, but notlimited to, ethylene glycol, methoxyethoxyethanol etc., or in an aproticsolvent such as tetrahydrofuran, dioxane, toluene, xylene, orN,N-dimethyformamide, facilitated by the optional use of a base such assodium hydride (NaH), lithium diisopropylamide (LDA), which arepreferred. The coupled product (V) was treated with a base such as NaHor LDA in an aprotic solvent such as tetrahydrofuran (THF) orN,N-dimethylformamide (DMF) or in a combination of potassiumtert-butoxide in t-butanol (tBuOK/tBuOH) followed by an alkylating agentR⁴L′, such as an alkyl iodide, mesylate or tosylate to afford thecorresponding alkylated product of Formula (I).

The compounds of Formula (I), wherein V and Y are N and Z, J, K, and Lare all CH, can be prepared as shown in Scheme 2. The substitutedaniline (VI) was converted to the corresponding guanidinium salt (VII)by treatment with the appropriate reagent such as cyanamide.

The guanidinium salt (VII) was reacted with a β-diketone (VIII) in thepresence of a base such as potassium carbonate (K₂CO₃) inN,N-dimethylformamide (DMF) or in an alcoholic solvent in the presenceof the corresponding alkoxide to afford the corresponding pyrimidine(IX). This was subsequently alkylated to provide (X), a compound ofFormula (I) wherein X′ is hydrogen, by conditions identical to thosedescribed in Scheme 1.

Compounds of the Formula (I), wherein V and Y are N and Z, J, K, and Lare all CH and R³ is NR⁶R⁷, can be prepared as shown in Scheme 3.Treatment of 2,4-dichloro-6-alkylpyrimidine (XI) with a primary orsecondary amine in the presence of a non-nucleophilic base such as atrialkylamine afforded selectively the corresponding 4-substituted aminoadduct (XII).

This in turn, was reacted with the substituted aniline (IV) underconditions identical to those described in Scheme 1 to afford thecorresponding secondary pyrimidinamine (XIII). This was alkylated underconditions described in Schemes 1 and 2.

Compounds of Formula (I) wherein J, K, and L are CH and Z is CR² and Vand Y are N can also be prepared by the route outlined in Scheme 4. Theguanidinium salt (XII) was reacted with a β-ketoester (XV) in thepresence of a base such as an alkoxide in the corresponding alcoholicsolvent to give the adduct (XVI). Treatment of the hydroxy group in(XVI) with either phosphorous oxychloride, phosphorous oxybromide,methanesulfonyl chloride, p-toluenesulfonyl chloride, ortrifluoromethanesulfonic anhydride provided (XVII), wherein the L is aleaving group and is, respectively, Cl, Br, I, OMs, OTs, or OTf. The Lgroup of (XVII) was displaced with a nucleophile such as NR⁶R⁷, OR⁶,SR⁶, CN, an organolithium, organomagnesium, organosodium,organopotassium, an alkyl cuprate, or in general an organometallicreagent to the corresponding adduct (IX), which was further alkylatedunder the standard conditions to produce (XVIII).

Compounds of the Formula (I) that are substituted at the 2-position ofthe phenyl ring could be prepared as outlined in Scheme 5.

Compounds of the Formula (I) wherein X is other than bromine can beprepared by the intermediates shown in Scheme 5. Reaction of the 2-halocompound (V) wherein X is bromine or hydrogen with a metalating agentsuch as, but not limited to, n-BuLi or t-BuLi in an aprotic solvent,preferably ether or tetrahydrofuran, provided the corresponding 2-lithiointermediate (X=Li, not isolated) which was further reacted with anelectrophile such as iodine or trimethyltin chloride ((CH₃)₃SnCl) togive the corresponding 2-substituted product (XIX). These intermediatescan also be further reacted using palladium-catalyzed coupling reactionswell known to one of skill in the art to prepare the compounds of theinvention.

Compounds of the Formula (I) wherein Z, K and L are all CHI, J is N orCH, and R′ is ethyl can be prepared as illustrated in Scheme 6.Sequential addition/re-oxidation of an alkyllithium to2-chloropyrimidine can provide intermediate (XXII) wherein the R¹ and R³can be independent of one another. Displacement of the chlorine by asuitable nitrogen nucleophile such as an aniline under similarconditions of Scheme 1, followed by attachment of the R⁴ group byalkylation in an analogous method of Schemes 1 or 2 can provide thecompounds of the invention.

Compounds of the Formula (I) wherein Z is N can be prepared according tothe method outlined in Scheme 7. Known triazine (XXIII), synthesis ofwhich is reported in J. Amer. Chem. Soc. 77:2447 (1956), can be reactedwith a substituted aniline (IV) in a analogous manner to Scheme 1.Similarly, the 2,4 dichloro 6-methyltriazine, which can be prepared viathe method reported in U.S. Pat. No. 3,947,374 can be coupled to thesubstituted aniline (IV) to provide (XXIV) where R³ is chlorine.Nucleophilic addition in protic or aprotic solvents allows for a varietyof substituents at this position (XXV). Alkylation of the secondaryamine as previously described provide triazine compounds of formula (I).

Compounds wherein R³ is carboxy-derived are synthesized according toScheme 8. A pyrimidine ester of formula (XXVI), which is prepared by theliterature method reported in Budesinsky and Roubinek, Collection.Czech. Chem. Comm. 26:2871-2885 (1961) is reacted with an amine offormula (IV) in the presence of an inert solvent to afford anintermediate of formula (XXVII). Inert solvents include lower alkylalcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclicethers of 4 to 10 carbons (preferably dioxane), dialkylformamides(preferably N,N-dimethylformamide), dialkylacetamides, (preferablyN,N-dimethylacetamide), cyclic amides, (preferablyN-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethylsulfoxide), hydrocarbons of 5 to 10 carbons or aromatic hydrocarbons of6 to carbons. Compounds of formula (XXVII) are treated with a base and acompound of Formula R⁴X, where X is halogen (preferably Cl, Br or I) inan inert solvent. Such bases include a tertiary amine, an alkali metalhydride

(preferably sodium hydride), an aromatic amine (preferably pyridine), oran alkali metal carbonate or alkoxide. The choice of inert solvent mustbe compatible with the choice of base (see J. March, Advanced OrganicChemistry (New York: J. Wiley and Sons, 1985) pp. 364-366, 412; H. O.House, Modern Synthetic Reactions (New York: W. A. Benjamin Inc., 1972,pp. 510-536)). Solvents include lower alkyl alcohols of 1 to 6 carbons,lower alkanenitriles (preferably acetonitrile), dialkyl ethers of 4 to10 carbons, cyclic ethers of 4 to 10 carbons (preferably tetrahydrofuranor dioxane), dialkylformamides (preferably N,N-dimethylformamide),cyclic amides, (preferably N-methylpyrrolidinone), dialkyl sulfoxides(preferably dimethyl sulfoxide), hydrocarbons of 5 to 10 carbons oraromatic hydrocarbons to 6 to 10 carbons. Esters of formula (XXVIII) maybe converted to acids of formula (XXIX) by acidic or basic hydrolysis(cf. J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons,1985) pp. 334-338) or by treatment with an alkali metal salt (preferablyLiI or NaCN) in the presence of an inert solvent at temperatures rangingfrom 50 to 200° C. (preferably 100 to 180° C.) (cf. McMurray, J. E.Organic Reactions, Dauben, W. G. et al., eds., J. Wiley and Sons, NewYork (1976), Vol. 24, pp. 187-224). Inert solvents includedialkylformamides (preferably N,N-dimethylformamide), dialkylacetamides,(preferably N,N-dimethylacetamide), cyclic amides, (preferablyN-methylpyrrolidinone), and dialkyl sulfoxides (preferably dimethylsulfoxide), or aromatic amines (preferably pyridine). Acids of formula(XXIX) may be treated with a halogenating agent to give an acid halide,which may or may not be isolated, then reacted with an amine of formulaHNR⁶R⁷, with or without an inert solvent, with or without a base, astaught by the literature (J. March, Advanced Organic Chemistry, J. Wileyand Sons, New York (1985), pp. 370-373, 389), to provide amides offormula (XXX). Halogenating agents include thionyl chloride (SOCl₂),oxalyl chloride ((COCl)₂), phosphorous trichloride (PCl₃), phosphorouspentachloride (PCl₅), or phosphorous oxychloride (POCl₃). Inert solventsinclude lower halocarbons of 1 to 6 carbons and 2 to 6 halogens(preferably dichloromethane or dichloroethane), dialkyl ethers of 4 to10 carbons, cyclic ethers of 4 to 10 carbons (preferably dioxane) oraromatic hydrocarbons to 6 to 10 carbons. Bases include trialkyl aminesor aromatic amines (preferably pyridine). Alternatively, esters offormula (XXVIII) may be reacted with an amine of formula HNR⁶R⁷, with orwithout an inert solvent, with or without a base, as taught by theliterature (cf. J. March, Advanced Organic Chemistry (New York: J. Wileyand Sons, 1985) pp. 370-373, 389) to generate amides of formula (XXX).Solvents include lower alkyl alcohols of 1 to 6 carbons, loweralkanenitriles (preferably acetonitrile), dialkyl ethers of 4 to 10carbons, cyclic ethers of 4 to 10 carbons (preferably tetrahydrofuran ordioxane), dialkylformamides (preferably N,N-dimethylformamide),dialkylacetamides, (preferably N,N-dimethylacetamide), cyclic amides,(preferably N-methylpyrrolidinone), dialkyl sulfoxides (preferablydimethyl sulfoxide), hydrocarbons of 5 to 10 carbons or aromatichydrocarbons to 6 to 10 carbons. Such bases include a tertiary amine, analkali metal hydride (preferably sodium hydride), an aromatic amine(preferably pyridine), or an alkali metal carbonate or alkoxide. Amidesof formula (XXX) may be treated with a reducing agent in an inertsolvent to provide amines of formula (XXXI). Such reducing agentsinclude, but are not limited to, alkali metal aluminum hydrides,preferably lithium aluminum hydride, alkali metal borohydrides(preferably lithium borohydride), alkali metal trialkoxyaluminumhydrides (such as lithium tri-t-butoxyaluminum hydride), dialkylaluminumhydrides (such as di-isobutylaluminum hydride), borane, dialkylboranes(such as di-isoamyl borane), alkali metal trialkylboron hydrides (suchas lithium triethylboron hydride). Inert solvents include lower alkylalcohols of 1 to 6 carbons, ethereal solvents (such as diethyl ether ortetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10carbons. Reaction temperatures for the reduction range from about −78°to 200° C., preferably about 50° to 120° C. The choice of reducing agentand solvent is known to those skilled in the art as taught in the abovecited March reference (pp. 1093-1110).

Scheme 9 depicts the synthesis and chemical modifications to formcompounds of formula (XXXIII). Esters of formula (XXVIII) or acids offormula (XXIX) may be treated with a reducing agent in an inert solventto provide alcohols of formula (XXXII). Such reducing agents include,but are not limited to, alkali metal aluminum hydrides, preferablylithium aluminum hydride, alkali metal borohydrides (preferably lithiumborohydride), alkali metal trialkoxyaluminum hydrides (such as lithiumtri-t-butoxyaluminum hydride), dialkylaluminum hydrides (such asdi-isobutylaluminum hydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal trialkylboron hydrides (such as lithiumtriethylboron hydride). Inert solvents include lower alkyl alcohols of 1to 6 carbons, ethereal solvents (such as diethyl ether ortetrahydrofuran), aromatic or non-aromatic hydrocarbons of 6 to 10carbons. Reaction temperatures for the reduction range from about −78°to 200° C., preferably about 50° to 120° C. The choice of reducing agentand solvent is known to those skilled in the art as taught in the abovecited March reference (pp. 1093-1110). Alcohols of Formula (XXXII) maybe converted to ethers of formula (XXXIII) by treatment with a base anda compound of Formula R⁸X, where X is halogen. Bases which may be usedfor this reaction include, but are not limited to, alkali metalhydrides, preferably sodium hydride, alkali metal carbonates, preferablypotassium carbonate, alkali metal dialkylamides, preferably lithiumdi-isopropylamide, alkali metal bis-(trialkylsilyl)amides, preferablysodium bis-(trimethylsilyl)amide, alkyl alkali metal compounds (such asbutyl lithium), alkali metal alkoxides (such as sodium ethoxide), alkylalkaline earth metal halides (such as methyl magnesium bromide),trialkylamines (such as triethylamine or di-isopropylethylamine),polycyclic di-amines (such as 1,4 diazabicyclo[2.2.2]octane or1,8-diazabicyclo-[5.4.0]undecene) or quaternary ammonium salts (such asTriton B). The choice of inert solvent must be compatible with thechoice of base (J. March, Advanced Organic Chemistry (New York: J. Wileyand Sons, 1985) pp. 255-446; H. O. House, Modern Synthetic Reactions(New York:

W. A. Benjamin Inc., 1972, pp. 546-553)). Solvents include lower alkylalcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, cyclicethers of 4 to 10 carbons, preferably tetrahydrofuran or dioxane,dialkylformamides, preferably N,N-dimethylformamide, dialkylacetamides,preferably N,N-dimethylacetamide, cyclic amides, preferablyN-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons or aromatichydrocarbons to 6 to 10 carbons.

Alternatively, compounds of formula (XXXII) may be converted tocompounds of formula (XXXIV), where Y is halide, arylsulfonyloxy(preferably p-toluenesulfonyloxy), alkylsulfonyloxy (such asmethanesulfonyloxy), haloalkylsulfonyloxy (preferablytrifluoromethyl-sulfonyloxy), by reaction with a halogenating agent or asulfonylating agent. Examples of halogenating agents include, but arenot limited to, SOCl₂, PCl₃, PCl₃, POCl₃, Ph₃P—CCl₄, Ph₃P—CBr₄,Ph₃P—Br₂, Ph₃P—I₂, PBr₃, PBr₅. The choice of halogenating agents andreaction conditions are known to those skilled in the prior art (Marchreference, pp. 382-384). Sulfonylating agents include, but are notlimited to, (lower alkyl)sulfonyl chlorides (preferably methanesulfonylchloride), (lower haloalkyl) sulfonic anhydrides (preferablytrifluoromethylsulfonic anhydride, phenyl or alkyl substituted-phenylsulfonyl chlorides (preferably p-toluenesulfonyl chloride). Thesulfonylation or halogenations may require a base as taught by theliterature (March reference, pp. 1172, 382-384). Such bases include atertiary amine, an alkali metal hydride (preferably sodium hydride), anaromatic amine (preferably pyridine), or an alkali metal carbonate oralkoxide. Solvents for the halogenation or sulfonylation should be inertunder the reaction conditions as taught by the literature. Such solventsinclude lower halocarbons (preferably dichloromethane ordichloroethane), or ethereal solvents (preferably tetrahydrofuran ordioxane). Intermediates of formula (XXXIV) may then be converted tocompounds of formula (XXXIII) by treatment with a compound of formulaR⁸OH with or without a base, in an inert solvent (March reference, pp.342-343). Such bases include alkali metal hydrides, preferably sodiumhydride, alkali metal carbonates, preferably potassium carbonate, alkalimetal dialkylamides, preferably lithium diiisopropylamide, alkali metalbis-(trialkylsilyl)amides, preferably sodium bis-(trimethylsilyl)amide,alkyl alkali metal compounds (such as n-butyllithium), alkali metalalkoxides (such as sodium ethoxide), alkyl alkaline earth metal halides(such as methyl magnesium bromide), trialkylamines (such astriethylamine or di-isopropylethylamine), polycyclic diamines (such as1,4 diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]undecene) orquaternary ammonium salts (such as Triton B). Solvents include loweralkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons,cyclic ethers of 4 to 10 carbons, preferably tetrahydrofuran or dioxane,dialkylformamides, preferably N,N-dimethylformamide, dialkylacetamides,preferably N,N-dimethylacetamide, cyclic amides, preferablyN-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons or aromatichydrocarbons to 6 to 10 carbons.

Intermediates of formula (XXXIII) may be prepared from intermediates offormula (XXXII) by reaction with a triarylphosphine (preferablytriphenylphosphine), a di-(lower alkyl) azodicarboxylate) and a compoundof formula R⁸OH in the presence of an inert solvent as described in thegeneral literature (Mitsunobu, O., Synthesis 1:1-28 (1981)).

Compounds of formula (XXXI) may be prepared by treatment of a compoundof formula (XXXIV) with a compound of Formula HNR⁶R⁷, with or without abase, in an inert solvent (Scheme 9). Such bases and inert solvents maybe the same ones used for the transformation of compounds (XXVIII) tocompounds (XXX) in Scheme 8.

Compounds of Formula (I) which are substituted at the 4-position of thepyrimidine ring can be prepared as outlined in Scheme 10.

Known pyrimidine (XXXV), synthesis of which is reported in Eur. J. Med.Chem. 23:60 (1988), can be reacted with a substituted aniline (IV) in ananalogous manner to Scheme 1. Treatment of the hydroxy group in (XXXVI)with either phosphorous oxychloride, phosphorous oxybromide,p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydrideprovided (XXXVII), wherein the L is a leaving group. Alkylation underthe standard conditions gives (XXXVIII). The L group of (XXXVIII) wasdisplaced with a nucleophile such as NR⁶R⁷, OR⁶, SR⁶, CN, or anorganometallic reagent to the corresponding adduct (XXXIX).

Compounds of the Formula (I), wherein X or X′ is alkylmercapto, orfunctionalized alkylmercapto can be synthesized under the conditionsdescribed in Scheme 11.

Treatment of the appropriately ortho-functionalized aniline XXXIX with asubstituted 2-mercaptopyrimidine XL in the presence of a base such aspotassium carbonate, sodium carbonate, alkali metal alkoxide, potassiumsodium or lithium hydride, a lithium, sodium or potassium dialkylamide,or an alkali metal in the presence of copper powder or copper saltsgives the corresponding aryl sulfide XLI which is subjected to a Smilesrearrangement by treatment with an strong acid such as hydrochloric,hydrobromic, hydriodic, sulfuric, phosphoric or perchloric, to give thecorresponding disulfide XLIII. This is reduced to the sulfide XLIV witha reducing agent such as sodium borohydride and alkylated on the sulfurwith the appropriate alkylating agent such as an alkyl halide, tosylateor mesylate. The rearrangement of XLI may be carried out with a strongbase such as lithium, sodium, or potassium hydride; lithium, sodium, orpotassium dialkylamide; or lithium sodium or potassium metal, in anappropriate solvent such as decahydronaphthalene, xylenes, high boilingalcohols, dimethylformamide, dimethylsulfoxide, dimethylacetamide, andN-methylpyrrolidinone. The rearrangement product can be selectivelyalkylated on the sulfur with the use of a base such as potassium, sodiumor lithium carbonate, potassium, sodium or lithium alkoxide, ortrialkylamine and the appropriate alkylating agent as described above.The alkylsulfide can be further alkylated on the nitrogen by usingidentical conditions as described above to yield compound XLV.

Compounds of formula (I), wherein R³ is (CH₂)_(k)OR⁸ and R⁸ is(CH₂)_(t)C(═O)OR²⁴, (CH₂),C(═O)NR⁶R⁷, or (CH₂)_(t)NR⁶R⁷ can be madeaccording to Scheme 12.

Compounds XLVII, XLVIII, and XLIX are made using the product of Example24 as starting material by procedures analogous to those used to makethe products of Examples 25, 16, and 17 respectively.

The novel 7-azaindoles of the present invention are prepared by Scheme13 outlined below. The potassium salt of formylsuccinonitrile is treatedwith the appropriate substituted aniline L to give LI. This undergoesbase catalyzed cyclization to a 1-aryl-2-amino-4-cyanopyrrole LII.Reaction with an appropriate 1,3-dicarbonyl compound gives the desired7-azaindole LIII.

The nitrile substituent at position 3 of structure LIII is readilyremoved by refluxing the 3-cyano compound with 65% sulfuric acid.Position 3 then can be resubstituted by halogenation or nitration.Reduction of the nitro group can provide the 3-amino substituent.

Alternatively, the nitrile group can be converted to desired L groups bymethods described in “Comprehensive Organic Transformations”, by RichardC. Larock, VCH Publishers, Inc., New York, N.Y., 1989. For instance, thenitrile group can be reduced with diisobutylaluminum hydride to give the3-aldehyde. The 3-aldehyde can be reduced via the hydrazone underWolff-Kishner conditions (KOH in hot diethylene glycol) to giveL=methyl. Furthermore, the aldehyde can be converted to L═CH═CH₂ byadding it to a mixture of methyltriphenylphosphonium bromide andpotassium tertiary-butoxide in tetrahydrofuran (Wittig reaction).Reduction of the ethenyl group to give L═CH₂CH₃ can be effected byhydroboration-protonolysis (J. Am. Chem. Soc. 81:4108(1959)).

Scheme 13 generally provides a mixture isomeric in substituents R¹ andR³, which then can be separated, Sometimes the preferred isomer is theone obtained in lower yield. In that event Scheme 14 can be used toprepare the preferred isomer. Intermediate LII is treated with theappropriate acyl- or aroyl-acetic ester under either thermal oracid-catalyzed conditions to give the 6-hydroxy compound LV. Compound LVis converted to the 6-chloro compound LVI and de-cyanylated to compoundLVII. When R¹ substituents other than chloro are desired, the chlorogroup can be converted to other substituents. For instance, treatment ofcompound LVII with an alkyl Grignard reagent can provide compound LVIIIwhere R¹=alkyl. Heating with a primary or secondary amine can providecompound LVIII where R¹=amino.

Scheme 15 affords another route to compounds of this invention.Intermediate LII can be treated with the appropriate acylacetaldehydedialkyl acetal under acid catalyzed conditions to give compounds LXa andLXb, 7-azaindoles unsubstituted at positions 4 and 6 respectively.Compound LXa can be oxidized with m-chloroperoxybenzoic acid to give theN-oxide compound LXI. Heating compound LXI with phosphorus oxychloridecan give compound XIIa, which can be decyanylated to compound LXIII.

Compound LXIV where R³ is an amino substituent can be prepared byheating LXIII with the appropriate amine; where R³=alkoxide, the metalalkoxide can be heated with LXIII; where R³=aryl, compound LXIII cantreated with the arylboronic acid in the presence oftetrakis(triphenylphosphine)p alladium (TTPP) and sodium carbonate; andwhere R³=alkyl, alkenyl, aralkyl, and cycloalkyl, compound LXIII can becoupled with the appropriate organotin reagent, also in the presence of7TPP.

Compound LXIV where R³ is a nitro group can be prepared by nitration ofLXI, decyanylation, and reduction of the N-oxide with a trivalentphosphorus compound such as triethyl phosphite.

Compound LXb can be substituted in the 6 position using methodsdescribed for the substitution of LXa.

The novel 7-azabenzimidazoles of this invention can be prepared asoutlined in Scheme 16 where R²⁹ is nitrogen. Compounds L and LXV canreact upon heating in the presence of a base, e.g. sodium hydride, togive the diarylamine LXVI. Reduction of the nitro group with stannouschloride can give LXVII, which can be closed to the 7-azabenzimidazoleLXVIII.

The purines of this invention can be prepared as shown in Schemes 17 and18.

Compounds L and LXIX (J. Heterocyclic Chem. 28:465 (1991)) can be heatedin the presence of a base, e.g. sodium hydride, to give compound LXX.Heating LXX with the appropriate carboxylic acid in the presence of amineral acid catalyst can give LXXI where R²⁸ is hydrogen, alkyl,alkenyl, or alkynyl. The chloro substituent can then be converted to R³to give compounds LXXII by using one of the methods described above forthe introduction of R³ to obtain compounds LXIV.

Scheme 18 can be used to prepare purines where R²⁸ is halogen oralkoxide. Compounds LXX can be heated with a dialkyl carbonate, such asdiethyl carbonate, to give the carbonyl compound LXXIII; if theconversion is undesirably slow, more reactive species such astrichloromethyl chlorocarbonate or carbonyl diumidazole can be used inplace of diethyl carbonate. The chloro substituent can then be convertedto R³ to give LXXIV by using one of the methods described above for theintroduction of R³ to obtain LXIV. Heating LXXIV with phosphorusoxychloride can give the 2-chloropurine, LXXV. To prepare the2-alkoxypurines, LXXVI, LXXV can be heated with a metal salt of thealcohol R³¹OH, e.g. the sodium or potassium salt, wherein in R³¹ isC₁-C₄ alkyl.

The method of synthesis of the 7-azaindolines of this invention is shownin Scheme 19.

A number of compounds of the general structure LXXVIII with desired R¹and R² groups have been described by W. Paudler and T.-K. Chen, J.Heterocyclic Chem. 7:767 (1970). These can be oxidized with a peracid,e.g. m-chloroperoxybenzoic acid, to the sulfone LXXIX. Sulfone LXXIX canbe heated in the presence of the desired aniline and a base, e.g. sodiumhydride to give the diaryl amine LXXX. Alkylation of LXXX with thedesired unsubstituted or 4-substituted 3-butynyl iodide (or 3-butynolmesylate) can give LXXXI. LXXXI can undergo an intramolecularDiels-Alder reaction to give LXXXII.

In a number of cases, the desired 4-substituted 3-butynyl iodide is notreadily available or is unstable. In that event unsubstituted 3-butynyliodide is used to give compound LXXXII where R³=H.

The synthesis of the 5,7-diazaindoles of this invention is outlined inScheme 20.

The desired formamidine LXXXIII can be treated with LXXXIV in thepresence of sodium ethoxide in ethanol to give the pyrimidine LXXXV.Refluxing LXXXV in phosphorus oxychloride gives the dichloropyrimidineLXXXVI. Compound LXXXVI can be converted to the carbonyl compoundLXXXVII by treatment with one equivalent of ozone at −78° to give anozonide, which on treatment with sodium iodide and acetic acid gives thedesired carbonyl compound. The preparation of LXXXVII (R¹=H, R²⁸=CH₃ andR¹=R²⁸=CH₃) by a different route has been described by E. Basagni etal., Bull. Soc. Chim. Fr., 4338 (1969).

Before the coupling reaction, the carbonyl of compound LXXXVII isprotected by treatment with 2,2-dimethoxypropane in the presence of acatalytic amount of acid to give compound LXXXVIII. Compound LXXXVIII isthen coupled with the appropriate aniline L by heating in the presenceof a base, e.g. sodium hydride, to give compound LXXXIX. Compound LXXXIXcan be cyclized to give the 5,7-diazaindole XC, the target compoundwherein R³=Cl. Compound XC is also a useful intermediate for thepreparation of Compounds XCI with other R³ groups. For example, heatingthe chloro compound with the appropriate amine gives the desired aminocompound. Heating with a metal alkoxide gives the desired alkoxycompound. Treating compound XC (R³=Cl) with R³MgBr (R³=alkyl, aryl, oraralkyl) converts the chloro compound to the desired alkyl, aryl, oraralkyl compound XCI.

Compounds wherein R⁵ is dimethylhydroxymethyl, X′ is iodine and R¹ andR³ are chlorine can be prepared according to scheme 21. Ethyl4-aminobenzoate is iodinated in a methylene chloride/water (50:50)mixture in the presence of sodium bicarbonate to provide compound(XCII). This material is coupled to cyanuric chloride, then thesecondary amine is alkylated in an analogous manner to that in Scheme 1to yield XCIII. Compound XCIII is treated with 5 equivalents of MeMgBrto provide the desired material of formula (XCIV).

Scheme 22 depicts the synthesis of compounds of Formula (I), where Y=N,Z=CR² and R³ is COR²⁵, CH(OH)R²⁵ or C(OH)R²⁵R^(25a). An ester of Formula(XCVI) may be converted to an amide of Formula (C) by treatment with anamine of Formula HN(OR^(a))R^(b), where R^(a) and R^(b) are lower alkyl(preferably Me), in the presence of a trialkylaluminum reagent(preferably Me₃Al) in an inert solvent preferably an aromatichydrocarbon (e.g., benzene) or an ethereal solvent (e.g.,tetrahydrofuran) as taught by the prior art (cf. J. I. Levin, E. Turos,S. M. Weinreb, Synthetic Communications 12:989-993 (1982)). Amides ofFormula (C) may be converted to ketones of Formula (CI) by treatmentwith an organolithium reagent R²⁵Li or an organomagnesium halide R²⁵MgX,where X=Cl, Br or I, in an inert solvent, preferably an ethereal solvent(e.g., diethyl ether or tetrahydrofuran), as taught by the prior art(cf. S. Nahm and S. M. Weinreb, Tetrahedron Letters 22:3815-3818(1981)). Alternatively, ketones of Formula (CI) can be prepared fromacids of Formula (XCV) by treatment with an organolithium reagent R²⁵Liin the presence of an inorganic salt (preferably a transition metalhalide (e.g., CeCl₃)) in an inert solvent (preferably an etherealsolvent (e.g., tetrahydrofuran)) as taught by the prior art (cf. Y. Ahnand T. Cohen, Tetrahedron Letters 35:203-206 (1994)). Alternatively,esters of Formula (XCVI) can be converted directly to ketones of Formula(XCVIII) by reaction with an organolithium reagent R²⁵Li or anorganomagnesium halide R²⁵MgX, where X=Cl, Br or I, in an inert solvent(preferably an ethereal solvent e.g., diethyl ether or tetrahydrofuran)at temperatures ranging from −100 to 150° C. (preferably −78 to 80° C.)(cf. J. March, Advanced Organic Chemistry (New York: J. Wiley and Sons,1985, pp.433-434). Ketones of Formula (XCVIII) can be converted toalcohols of Formula (XCIX) by reaction with an organolithium reagentR²⁵Li or an organomagnesium halide R²⁵MgX, where X=Cl, Br or I, in aninert solvent (preferably an ethereal solvent (e.g. diethyl ether ortetrahydrofuran) at temperatures ranging from −100 to 150° C.(preferably −78 to 80° C.) (cf. the above March reference, pp. 434-435).Alternatively, esters of Formula (XCVI) can be converted to alcohols ofFormula (XCIX) by reaction with an organolithium reagent R^(25a)Li or anorganomagnesium halide R^(25a)MgX, where X=Cl, Br or I, in an inertsolvent (preferably an ethereal solvent e.g., diethyl ether ortetrahydrofuran) at temperatures ranging from −100 to 150° C.(preferably −78 to 100° C.), preferably using an excess amount oforganometallic reagent (cf. the above March reference, pp. 434-435). Inthis last instance, R²⁵=R²⁵. Ketones of Formula (XCVIII) can beconverted to alcohols of Formula (C) by treatment with a reducing agentin an inert solvent. Such reducing agents include, but are not limitedto, alkali metal aluminum hydrides, preferably lithium aluminum hydride,alkali metal borohydrides (preferably sodium borohydride), alkali metaltrialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminumhydride), dialkylaluminum hydrides (such as di-isobutylaluminumhydride), borane, dialkylboranes (such as di-isoamyl borane), alkalimetal trialkylboron hydrides (such as lithium triethylboron hydride).Inert solvents include lower alkyl alcohols of 1 to 6 carbons, etherealsolvents (such as diethyl ether or tetrahydrofuran), aromatic ornon-aromatic hydrocarbons of 6 to 10 carbons. Reaction temperatures forthe reduction range from about −78° to about 200° C., preferably about0° to about 120° C. The choice of reducing agent and solvent is known tothose skilled in the art as taught in the above cited March reference(Advanced Organic Chemistry, pp. 1093-1110).

Compounds of Formula (I) can also be prepared by the procedures outlinedin Scheme 23. A compound of Formula (CI) (Formula I, where Z=CR², Y=N,R³=(CHR¹¹)_(p)CN) can be reacted with sodium azide and ammonium chloridein a polar solvent at high temperatures (preferably 70 to 150° C.) togive a tetrazole of Formula (CII) as taught by the prior art (cf. R. N.Butler, Tetrazoles, in Comprehensive Heterocyclic Chemistry; A. R.Katritzky, C. W. Rees, Eds.; (New York: Pergamon Press, 1984), pp.828-832). Such polar solvents may be dialkylformamides (preferablyN,N-dimethylformamide), dialkylacetamides, (preferablyN,N-dimethylacetamide), cyclic amides, (preferablyN-methylpyrrolidinone), dialkyl sulfoxides (preferably dimethylsulfoxide) or dioxane. A compound of Formula (CIII) (Formula I, whereY=N, Z=CR² and R³=COCH₃) may be treated with a halogenating agent in aninert solvent to give a haloketone of Formula (CIV). Such halogenatingagents include bromine, chlorine, iodine, N-halosuccinimides (e.g.N-bromosuccinimide), N-halophthalimides (e.g., N-bromophthalimide) orN-tetrasubstituted ammonium perbromides (e.g., tetraethylammoniumperbromide) (cf. the above March reference, Advanced Organic Chemistry,pp. 539-531; S. Kajigaeshi, T. Kakinami, T. Okamoto, S. Fujisaki, Bull.Chem. Soc. Japan 60:1159-1160 (1987) and references cited therein).Inert solvents include lower halocarbons of 1 to 6 carbons and 2 to 6halogens (preferably dichloromethane or dichloroethane), dialkyl ethersof 4 to 10 carbons, cyclic ethers of 4 to 10 carbons (preferablydioxane) or aromatic hydrocarbons to 6 to 10 carbons. Haloketones ofFormula (CIV) may be converted to imidazoles of Formula (CVII) bytreatment with formamide with or without an inert solvent as taught bythe prior art (H. Brederick and G. Theilig, Chem. Ber. 86:88-108(1953)). Alternatively, ketones of Formula (CIII) may be converted tovinylogous amides (CV) by reaction with N,N-di(lower alkyl)formamidedi(lower alkyl)acetals (e.g., N,N-dimethylformamide dimethyl acetal) orGold's reagent ((dimethylaminomethyleneaminomethylene)-dimethylammoniumchloride) in an inert solvent with or without base as taught by theprior art (cf. J. T. Gupton, S. S. Andrew, C. Colon, SyntheticCommunications 12:35-41 (1982); R. F. Abdulla, K. H. Fuhr, J. OrganicChem. 43:4248-4250 (1978)). Such inert solvents include aromatichydrocarbons of 6 to 10 carbons, lower alkyl alcohols of 1 to 6 carbons,dialkyl ethers of 4 to 10 carbons, or cyclic ethers of 4 to 10 carbons(preferably dioxane). Such bases may include a tertiary amine, an alkalimetal hydride (preferably sodium hydride), an aromatic amine (preferablypyridine), or an alkali metal carbonate or alkoxide. Vinylogous amides(CV) can be condensed with hydrazine in an inert solvent to formpyrazoles of Formula (CVI) as taught by the prior art (cf. G. Sarodnick,Chemische Zeitung 115:217-218 (1991); Y. Lin, S. A. Lang, J.Heterocyclic Chem. 14:345 (1977); E. Stark et al., Chemische Zeitung101:161 (1977); J. V. Greenhill, Chem. Soc. Reviews 6:277 (1977)). Suchinert solvents include aromatic hydrocarbons of 6 to 10 carbons, loweralkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to 10 carbons, orcyclic ethers of 4 to 10 carbons (preferably dioxane).

The purines and 8-aza-purines of the present invention are readilysynthesized following the methods shown in Schemes 24 and 25. The purine(CXI) is derived from an appropriately substituted pyrimidine (CVIII).The trisubstituted hydroxypyrimidine is nitrated under standardconditions with fuming nitric acid. Following conversion of the hydroxycompound to the chloro derivative via treatment with phosphorusoxychloride, reduction of the nitro group with iron powder in aceticacid and methanol yielded the aminopyrimidine (CIIX). Compound CIIX isreacted with the appropriately substituted aniline in the presence ofbase catalyst to yield an anilinopyrimidine (CX), which was thenconverted to the desired purine (CXI) via reaction withtriethylorthoformate in acetic anhydride. Starting from compound CX, thedesired 8-aza-purine can be prepared via reaction with sodium nitrite inacetic acid.

If R³ of the purine is a chloro group, that substituent can be furtherelaborated to other R³ substituents as shown in Scheme 25. Compound(CXII), wherein R³ is chlorine, is reacted with a nucleophile with orwithout an inert solvent at temperatures ranging from 20° C. to 200° C.,to effect the formation of the 8-azapurine (CXIII). In a similarfashion, the R³ of an appropriately substituted purine (CXI) may beconverted to other functional groups to yield the purine (CXIV) havingthe desired substitution pattern. Similarly, if R¹ is a chloro group, itmay be converted to another functional group via reaction with anappropriate nucleophile. Nucleophiles include amine, hydroxy, ormercapto compounds or their salts.

Compounds of the Formula (I) wherein J, K, and/or L are N, such as(CXXVII), (CXXVIII), (CXXIX), or (CXXX), were prepared according toSchemes 26 and 27. The preparation of the lower ring heterocycle of thecompound of the Formula (I) is shown in Scheme 26.2,4-Dihydroxy-5-nitropyrimidine (CXV) was first converted to thedichloro compound (CXVI) via treatment with phosphorus oxychloride.Compound (CXVI) was then converted to the symmetrically bis-substitutedpyrimidines, (CXVII) and (CXVIII), via reaction with the appropriate R⁵or X group radicals, MR⁵ and MX, respectively, where M is a metal atom.It is understood that compounds of the Formula (I) wherein R⁵ and X havethe same definition fall within the scope of this invention. A method offorming the unsymmetrically bis-substituted compounds (CXIX) and (CXX)is treatment of (CXVI) with equimolar amounts of MR⁵ and X to form astatistical distribution of products, (CXVII), (CXVIII), (CXIX) and(CXX), which can be purified by standard techniques, such as,recrystallization or chromatography,

The desired (N-pyrimidino-N-alkyl)aminopyrimidines of the presentinvention were prepared according to Scheme 27. An appropriatelysubstituted 2-hydroxypyrimidine (CXXI) was converted to the2-chloropyrimidine (CXXII) via treatment with phosphorus oxychloride.The intermediate (N-pyrimidino)aminopyrimidines, (CXXIII), (CXXIV),(CXXV), and (CXXVI), were prepared via treatment of (CXXII) with theappropriate 5-aminopyrimidine, (CXVII), (CXVIII), (CXIX) and (CXX)respectively, in the presence of a base, such as, NaH. Simple alkylationof the amino groups in (CXXIII), (CXXIV), (CXXV), and (CXXVI) viatreatment with R⁴I and sodium hydride gave the desired(N-pyrimidino-N-alkyl)aminopyrimidines, (CXXVII), (CXXVIII), (CXXIX),and (CXXX).

The (N-heterocycle-N-alkyl)aminopyrimidines or N-heterocycle-N-alkyl)aminotriazines of the present invention may also be preparedaccording to Scheme 28. Commercially available amino substitutedheterocycles (CXXXI) may be brominated using a tetrasubstituted ammoniumtribromide, preferably benzyltrimethylammonium tribromide (BTMA Br₃) toyield the appropriately substituted o-bromo-aminoheterocycle (CXXXII).Such reactions are carried out in an inert solvent, such as, loweralcohols or halocarbons of 1 to 4 carbons and 1 to 4 halogens in thepresence of a base, such as, alkali metal or alkaline earth metalcarbonates. Compound (CXXXII) is then coupled to a substitutedpyrimidine or triazine (CXXXIII) to form an(N-heterocycle)aminopyrimidine (CXXXIVa) or (N-heterocycle)aminotriazine(CXXXIVb). (CXXXIVa or b) is then further alkylated in the presence of abase to the target (N-heterocycle-N-alkyl)aminopyrimidine (CXXXVa) or(N-heterocycle-N-alkyl)aminotriazine (CXXXVb), respectively.

The compounds of the invention and their syntheses are furtherillustrated by the following examples and preparations. All temperaturesare in degrees Celsius.

EXAMPLE 1N-(2-bromo-4-methylphenyl)-N-methyl-4,6-dimethyl-2-pymidinamine

Part A: To 4,6-dimethyl-2-hydroxypyrimidine (37.1 g), cooled in an icebath was slowly added phosphorous oxychloride (60 mL) and the mixturewas stirred at 0° C. for 15 minutes and heated to reflux for 23 hours.The mixture was allowed to cool to room temperature, poured slowly overice and extracted with diethyl ether (20×100 mL). The combined etherlayers were dried over magnesium sulfate and concentrated in vacuo toyield an off-white crystalline solid (19.77 g). The remaining materialwas subjected to lighter-than-water liquid/liquid extraction usingdiethyl ether for 19.5 hours to yield additional off-white crystallinesolid (3.53 g) after concentration. A total of 23.31 g of2-chloro-4,6-dimethylpyrimidine was obtained (55% yield).

Part B: To a solution of the product from Part A (2.0 g) in ethyleneglycol (80 mL) was added 2-bromo-4-methylaniline (2.6 g, 1 eq) and themixture was heated to reflux for 4.5 hours. After cooling to roomtemperature, the mixture was partitioned between water (200 mL) withethyl acetate (3×100 mL). The ethyl acetate layers were combined, washedwith brine, dried over magnesium sulfate, and concentrated under vacuumto yield a brown solid (4.92 g). This product was purified on a silicagel-60 column using 25% ethyl acetate in hexanes as eluent. Theintermediate, N-(2-bromo-4-methylphenyl)-4,6-dimethyl-2-pyrimidinamine(3.29 g) was obtained as light tan fine crystals (80% yield).

Part C: To the product from Part B (1.0 g) in dry tetrahydrofuran (40mL) was added potassium tert-butoxide in 2-methyl-2-propanol (1.0 M, 6.8mL) and iodomethane (1.0 mL, 5 eq). The mixture was stirred for 72 hoursat room temperature. After partitioning between water (50 ml) usingethyl acetate (2×100 ml), the ethyl acetate layers were combined, washedwith brine, dried over magnesium sulfate, and concentrated in vacuo toyield a yellow liquid (1.06 g). The crude product was purified on asilica gel-60 column using 15% ethyl acetate in hexanes as eluent. Thetitle compound, as the free base, was obtained as a thick yellow liquid(0.89 g; 85% yield). Anal. Calcd C₁₄H₁₆BrN₃: % C, 54.92; % H, 5.27; % N,13.72; ; % Br: 26.09. Found: % C, 54.61; % H, 5.25; % N, 13.55; % Br;26.32.

The hydrochloride salt was made using anhydrous hydrogen chloride indiethyl ether; mp 120-121° C.

EXAMPLE 2N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pymidinamine

Part A: A mixture of the product from Example 1, Part A (2.01 g, 14.01mmoles), 2-bromo-4-(1-methylethyl)aniline (3 g, 14.10 mmoles) inethylene glycol (20 mL) was heated to reflux for 1.5 hours. Followingcooling to room temperature and partitioning between ethyl acetate (200mL) and aqueous sodium hydroxide (1 M, 50 mL), the organic layer waswashed with brine, dried, and concentrated in vacuo. The residue waschromatographed on silica gel using 5% ethyl acetate in hexanes to give2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6-dimethylpyrimidinamine(3.28g).

Part B: The product from Part A (1.64 g, 5.12 mmoles) was treated withsodium hydride (60% in oil, 0.41 g, 10.25 mmoles) in tetrahydrofuran (10mL) at 25° C. for 15 minutes and iodomethane (0.82 mL, 13 mmoles) wasadded. The mixture was stirred at 25° C. for 90 hours and partitionedbetween ethyl acetate (100 mL) and water (30 mL). The water wasextracted with additional ethyl acetate (60 mL) and the combined organicextracts were washed with brine, dried, and concentrated in vacuo. Theresidue was chromatographed on silica gel using 8% ethyl acetate inhexanes to give the title compound (1.4 g) as the free-base.

The free-base was dissolved in ether (10 mL) and treated with a solutionof anhydrous hydrogen chloride in ether (1 M, 6 mL). The precipitatedsolid was collected and dried under vacuum (mp 163-164° C.).

EXAMPLE 3N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pypimidinamine

Part A: 2-Bromo-4-acetylacetanilide (2 g, 7.81 mmoles) was dissolved intrifluoroacetic acid (20 mL) and triethylsilane (2.8 mL, 17.5 mmoles)was added. The mixture became warm and was stirred without cooling for 4h. Then it was basified with conc. NH₄OH and NaHCO₃ and extracted withEtOAc (2×100 mL). The organic extracts were combined, washed with brine,dried and stripped in vacuo. The residue was >90% clean and directlyused in the next step.

Part B: Using the product from Part A and the procedure outlined forExample 1, the desired compound was obtained in good yield.

EXAMPLE 4N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-morpholino-6-methyl-2-pymidinamine

Part A: A mixture of 2,4-dichloro-6-methylpyrimidine (4 g, 24.54mmoles), morpholine (2.14 mL, 24.54 mmoles) andN,N-diisopropylethylamine (4.52 mL) in ethanol (60 mL) was stirred at 0°C. for 3 hours, 25° C. for 24 hours, followed by reflux for 1 hour. Thesolvent was removed under vacuum and the residue was partitioned betweenethyl acetate (200 mL) and aq. sodium hydroxide (1 M, 50 mL). Theorganic layer was washed with water and brine and dried and concentratedin vacuo. The residue was recrystallized from ethyl acetate/hexanes togive 2-chloro-4-morpholino-6-methylpyrimidine (3.8 g).

Part B: The product from Part A (1 g, 4.67 mmoles) and2-bromo-4-(1-methylethyl)aniline (1 g, 4.67 mmoles) were heated toreflux in ethylene glycol (6 mL) for 1.5 hours. After cooling, themixture was partitioned between ethyl acetate (100 mL) and aq. sodiumhydroxide (1 M, 20 mL). The organic layer was washed with water andbrine, dried and concentrated on a rotary evaporator. The residue waschromatographed on silica gel using 25% ethyl acetate in hexanes to give2-N-(2-bromo-4-(1-methylethyl)phenyl)-4-morpholino-6-methylpyrimidinamine(1.5 g).

Part C: The product from Part B (1.0 g, 2.56 mmoles) was treated withsodium hydride (60% in oil, 0.15 g, 3.75 mmoles) in tetrahydrofuran (10mL) at 25° C. for 20 minutes, followed by addition of iodoethane (0.32mL, 4 mmoles). The mixture was stirred at 25° C. for 24 hours and heatedto reflux for 5 hours. After partitioning between ethyl acetate (100 mL)and water (20 mL), the organic extract was washed with brine, dried, andconcentrated in vacuo. The residue was chromatographed on silica gelusing 12% ethyl acetate in hexanes to give the title compound (0.94 g)as the free-base.

The hydrochloride salt of the above title compound was prepared bydissolving the isolate in ether (10 mL) and treating with anhydroushydrogen chloride in ether (1 M, 4 mL). The precipitated solid wascollected and dried under vacuum (mp 219-222° C.).

EXAMPLE 5N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6dimethyl-2-pyrimidinamine

Part A: To a solution of 2-bromo-4-(1-methylethyl)aniline (6 g, 28.2mmoles) and cyanamide (4.7 g, 112.08 mmoles) dissolved in ethyl acetate(100 mL) and ethanol (13 mL) was added hydrogen chloride in ether (1 M,38 mL, 38 mmoles) and the mixture was stirred at 25° C. for 1 hour. Thevolume of the reaction was reduced by 75 mL by distillation. The residuewas heated to reflux for 3 hours and after cooling, ether (120 mL) wasadded. The precipitated solid,2-bromo-4-(1-methylethyl)phenylguanidinium hydrochloride, was collectedand dried (10.4 g), and was used in the next reaction withoutpurification.

Part B: A mixture of the product from Part A (5.0 g, 13.47 mmoles),potassium carbonate (1.86 g, 13.47 mmoles) and 2,4-pentanedione (2.8 mL,27.28 mmoles) in N,N-dimethylformamide (35 mL) was heated to reflux for24 hours. After cooling, the reaction was partitioned between ethylacetate (120 mL) and aq. sodium hydroxide (0.5 M, 100 mL). The aqueouslayer was extracted with additional ethyl acetate (120 mL) and thecombined organic extracts were washed with water, brine, dried andconcentrated in vacuo. The residue was chromatographed on silica geleluting with 8% ethyl acetate in hexanes to give2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6-dimethylpyrimidinamine (3.37g).

Part C: The product isolated from Part B (3.0 g, 9.37 mmoles) wasalkylated with sodium hydride and iodoethane in tetrahydrofuran in ananalogous manner to that described for Example 4, Part C. The titlecompound was isolated as the free-base (2.88 g).

The hydrochloride salt was prepared in a manner analogous to that ofExample 4 using hydrogen chloride in ether, to give a solid, mp 151-153°C.

EXAMPLE 6N-ethyl-N-(2-bromo-4-(2-methoxyethyl)phenyl)4-morpholino-6-methyl-2-pyrimidinamine

Part A: To 4-Hydroxyethylaniline, 16.55 g (0.12 moles) in a mixture ofpyridine (23 mL, 0.29 moles) and CH₂Cl₂ (100 mL) cooled to 0° C. wasadded acetyl chloride (18.8 mL, 0.26 moles) dropwise. The mixture wasstirred at 0° C. for 2 h and at 25° C. for 48 h and then added tosaturated NaHCO₃ solution (100 mL). The CH₂Cl₂ was separated, washedwith brine, dried and stripped in vacuo. The residue was chromatographedon silica gel using 25% and 1:1 EtOAc/hexanes to give the product (24 g,90% yield).

Part B: 4-Acetoxyethylacetanilide was brominated according to the methoddescribed in Org. Synth. Coll. Vol I, 111, wherein the anilide (14 g, 63mmoles) was dissolved in glacial acetic acid (70 mL) and bromine (4 mL,77.4 mmoles) was added dropwise. The resulting solution was stirred at25° C. for 60 hours. A solution of sodium sulfite (20 mL) was thenadded, followed by H₂O (200 mL) and the precipitated bromide wasisolated by filtration. The filtrate was further diluted with H₂O (300mL) and cooled to give an additional amount of bromide. The isolatedbromide was heated to reflux in HCl solution (6M, 100 mL) for 2 h andthe resulting mixture was neutralized with solid NaHCO₃ and extractedwith EtOAc (2×160 mL each). The combined EtOAc extracts were washed withbrine, dried and stripped in vacuo. The residue was chromatographed onsilica gel using 1:1 EtOAc/hexanes to give the product (2.8 g) in 20%yield for the two steps.

Part C: 2-Bromo-4-hydroxyethylaniline (1.6 g, 7.3 mmoles) and2-chloro-4,6-dimethylpyrimidine (1.1 g, 7.3 mmoles) were reacted inethylene glycol (6 mL) at reflux for 1.5 h. After cooling the mixturewas partitioned between EtOAc (100 mL) and NaOH solution (0.5M, 25 mL).The aqueous layer was extracted with additional EtOAc (50 mL) and thecombined organic extracts were washed with brine, dried and stripped invacuo. The residue was chromatographed on silica gel using 1:1EtOAc/hexanes to give the product (1.3 g) in 64% yield.

Part D: The product from Part C (1.39 g, 4.77 mmoles) was dissolved indry CH₂Cl₂ (30 mL) and 3,4-dihydro-2H-pyran (1.65 mL, 11.98 mmoles) wasadded, followed by conc. sulfuric acid (Conc. H₂SO₄, 0.2 mL). Themixture was stirred at 25° C. for 60 h and solid KpCp, (1 g) was added,followed by saturated NaHCO (50 mL), The mixture was partitioned between EtOAc (120 mL) and NaHCO₃ solution (20 mL). The EtOAc was washedwith brine, dried, and stripped in vacuo. The dried crude product,dissolved in dry THF (15 mL) was treated with sodium hydride (60% inoil, 380 mg) at 25° C. for 15 min and then iodoethane (1 mL, 9.45mmoles) was added.

The mixture was stirred at 25° C. for 12 h and heated to reflux for 4 h.Then it was partitioned between EtOAc (120 mL) and H₂O (20 mL). TheEtOAc was washed with brine, dried and stripped in vacuo. The residuewas chromatographed on silica gel using 15% EtOAc/hexanes to give theproduct (1.6 g) in 78% yield for the two steps.

Part E: The product from Part D was dissolved in MeOH (20 mL) and conc.H₂SO₄ (0.4 mL) was added, followed by HCl in ether (1M, 1.5 mL). Themixture was stirred at 25° C. for 2 h, quenched with solid K₂CO₃ (1 g),and partitioned between EtOAc (100 mL) and NaHCO₃ solution (30 mL) andNaOH solution (2 mL, 2 M). The H₂O layer was extracted with additionalEtOAc (60 mL) and the combined EtOAc extracts were washed with brine,dried, and stripped in vacuo. The residue was chromatographed on silicagel using 40% EtOAc/hexanes to give the product (1.23 g) in 95% yield.

Part F.: The product from Part E (720 mg, 2.06 mmoles) was treated withNaH (60% in oil, 120 mg, 3 mmoles) in THF (10 mL) at 0° C. for 5 min andat 25° C. for 15 min. lodomethane (0.25 mL, 4 mmoles) was added and theresulting mixture was stirred at 25° C. for 20 h. The reaction waspartitioned between EtOAc (100 mL) and H₂O (25 mL). The EtOAc was washedwith brine, dried, and stripped in vacuo. The residue waschromatographed on silica gel using 20% EtOAc/hexanes to give theproduct (680 mg) (91% yield), which was converted into the hydrochloridesalt by treatment with 1 M HCl/ether, mp 117-118.5° C.

EXAMPLE 7N-Ethyl-N-(2-iodo4-(1-methylethyl)phenyl)4-morpholinyl-6-methyl-2-pyrimidinamine

A solution of the free-based Example 4 (1.4 g, 3.34 mmoles) dissolved intetrahydrofuran (15 mL) at −78° C. was treated with n-butyllithium (1.6M in hexanes, 3.3 mL, 3.7 mmoles). After stirring 15 minutes, a solutionof iodine (1.0 g, 4 mmoles) in tetrahydrofuran (5 mL) was added dropwiseand the mixture was stirred at −78° C. for an additional 30 minutesbefore warming to 25° C. The reaction was partitioned between ethylacetate (100 mL) and sodium bisulfite solution (satd., 20 mL). The ethylacetate layer was washed with water, brine, dried and concentrated invacuo. The residue was chromatographed on silica gel using 15% ethylacetate in hexanes as eluent to give the title compound (0.9 g) as asolid, mp 96-98° C.

EXAMPLE 8N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(2-thienyl)-2-pyrimidinamine

Part A: 2-Chloropyrimidine (2.0 g) was dissolved in diethyl ether (50mL) and chilled to −30° C. A solution of methyllithum in ether (1.4molar, 15 mL) was slowly added and the reaction was stirred at −30° C.for 30 minutes, then at 0° C. for an additional 30 minutes. A mixture ofacetic acid (glacial, 1.2 mL), water (0.5 mL) and tetrahydrofuran (5 mL)was added to quench the reaction.2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (4.79 g) in tetrahydrofuran(20 mL) was then added and the reaction was allowed to stir for 5minutes at room temperature. The mixture was chilled to 0° C. andaqueous sodium hydroxide solution (3 M, 50 mL) was added and thereaction mixture allowed to stir for 10 minutes. The organic layer wasseparated and washed with water and dried with magnesium sulfate. Thesolvent was removed in vacuo and the resulting residue chromatographedon silica gel (solvent 30% ethyl acetate in hexanes; R_(f) 0.4) to yield2-chloro-4-methylpyrimidine (1.4 g), m.p. 48-50° C.

Part B: To thiophene (0.66 g) in dry ether (25 mL) at 0° C. was addedn-butyl lithium in hexanes (1.6 M, 2.7 mL) and the reaction was stirredat 0° C. for 15 minutes. After cooling to −30° C., a solution of2-chloro-4-methylpyrimidine (1.0 g) in ether (10 mL) was slowly addedand the reaction was stirred at −30° C. for 30 minutes and at 0° C. anadditional 30 minutes before quenching with a mixture of acetic acid(glacial, 0.45 mL), water (0.5 mL) and tetrahydrofuran (1.0 mL).2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.77 g) in tetrahydrofuran (5mL) was added and the reaction mixture was stirred at room temperaturefor 5 minutes, then cooled to 0° C. before aq. sodium hydroxide solution(3 M, 50 mL) was added. The organic layer was separated, washed withwater, and dried with magnesium sulfate. The solvent was evaporated andthe resultant crude oil was chromatographed on silica gel (30% ethylacetate in hexanes; R_(f) 0.55) to yield2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g). Anal. Calcd: % C,51.46; % H, 3.33; % N, 13.33. Found: % C, 51.77; % H, 3.35; % N, 12.97.

Part C; 2-Bromo-4-(1-methylethyl)aniline (0.26 g) and2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g) in ethylene glycolwere heated at reflux for 24 hours. The reaction mixture was dilutedwith ethyl acetate, washed with aq. sodium hydroxide solution (10% ,3×100 mL) and the organic phase was dried. Solvent removal gave a crudebrown oil, which was purified on silica gel using 20% ethyl acetate inhexanes (R_(f) 0.5) as eluent to provideN-(2-bromo-4-isopropylphenyl)-4-methyl-6-(2-thienyl)-2-pyrimidinamine(0.1 g) as a solid, mp 98-101° C. Mass spec (NH₃-CI/DDIP): 390 (M+H)³⁰ .

Part D: The product from Part C (0.1 g) was slowly added to a solutionof sodium hydride (50 mg) in dry tetrahydrofuran, after which iodoethane(0.1 g) was added and the mixture was refluxed for 24 hours. Thereaction mixture was cooled and water (0.5 mL) was added. The solventwas evaporated and the crude material was taken up in ethyl acetate,washed with water (3×50 mL) and dried. The solvent was evaporated andthe crude product chromatographed on silica gel using 10% ethyl acetatein hexanes (R_(f)0.5) to give the title compound (70 mg) as thefree-base.

The HCl salt of this material was prepared using the procedure reportedabove; mp 95-97° C.; Mass spec. (NH₃-CI/DDIP): 417 (M+H)⁺. Anal. Calcdfor C₂₀,H₂₂N₃BrS.HCl: % C, 53.10; % H, 5.09; % N, 9.51. Found: % C,53.78; % H, 5.22; % N, 9.10.

EXAMPLE 9N-(2-Bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyrimidinamine)

By analogy to Example 2 the title compound was prepared by substituting2-bromo-4-(1-methylethyl)aniline (4.0 g) and2-chloro-4,6-dimethylpyrimidine in Part A, to give the desiredpyrimidinamine intermediate, Mass spec. (NH₃-CI/DDIP): 321 (M+H)⁺. Bysubstituting (bromomethyl)cyclopropane in Part B of this same Example,the desired material was obtained, Mass spec. (NH₃-CI/DDIP): 374 (M+H)⁺.

The hydrochloride salt of this free base was prepared, mp 146-148° C.

EXAMPLE 10N-(2-Bromo-4-(1-methylethyl)phenyl)-N-propargyl4,6-dimethyl-2-pyrimidinamine

By using 2-(2-bromo-4-(1-methylethyl)anilino)-4,6-dimethylpyrimidine andsubstituting propargyl chloride in Example 9, the title compound wasisolated as the free-base, Mass spec. (NH₃-CI/DDIP): 358 (M+H)⁺.

The hydrochloride salt of the free base was prepared.

EXAMPLE 11N-Ethyl-N-(2-iodo4-(2-methoxyethyl)phenyl)4,6-dimethyl-2-pyrimidinamine,hydrochloride

Part A: 4-Hydroxyethylaniline was iodinated in a manner analogous tothat described in Example 6 in conjunction with that reported in Tet.Lett. 33:373-376 (1992). The aniline (2 g, 14.58 mmoles) was dissolvedin CH₃CN (25 mL) and H₂O (15 mL) containing NaHCO₃ (1.68 g, 20 mmoles)was added. The mixture was cooled to 12-15° C. by addition of ice andiodine (3.9 g, 15.35 mmoles) was added. The mixture was stirred at 25°C. for 16 h and then it was partitioned between EtOAc (100 mL) and NaOHsolution (20 mL, 1M). The EtOAc was washed with brine, dried andstripped in vacuo. The residue was chromatographed on silica gel using1:1 EtOAc/hexanes to give 1.8 g product, a 47% yield.

Part B: The product from Part A (6.3 g, 23.94 mmoles) was dissolved in amixture of EtOAc (100 mL) and EtOH (10 mL) and cyanamide (4.7 g, 112.5mmoles) was added, followed by HCl in ether (31 mL, 1 M). The flask wasfitted with a distillation head and 50 mL solvent was distilled off. Theresidual mixture was diluted with EtOH (15 mL) and heated to reflux for5 h. After cooling, Et₂O (100 mL) was added and the precipitated saltwas washed with EtOAc and dried to give the product (4.5 g) in 55%yield.

Part C: The guanidinium salt from Part B (8.53 g, 24.95 mmoles),potassium carbonate (3.84 g, 27.72 mmoles) and 2,4-pentanedione (9 mL,42.65 mmoles) were heated to reflux in DMF (70 mL) for 16 h. Thereaction mixture was partitioned between EtOAc (150 mL) and H₂O (50 mL)and the organic layer was washed with H₂O (2×80 mL), brine, dried andstripped in vacuo. The residue was chromatographed on silica gel using1:1 EtOAc/hexanes to give the product (2.8 g) in 30% yield.

Part D: To the product from Part C (3.3 g (8.93 mmoles) in CH₂Cl₂ (60mL) and 3,4-dihydro-2H-pyran (3.1 mL, 22.7 mmoles) was added Conc. H₂SO₄(0.5 mL) and the mixture was stirred at 25° C. for 16 h. An additionalportion of H₂SO₄ (0.2 mL) was added and stirring was continued for 3 h.EtOAc (100 mL) and saturated NaHCO₃ (100 mL) was added and the layersseparated. The aqueous layer was extracted with additional EtOAc (100mL) and the combined organic extracts were washed with NaHCO₃, brine,dried and stripped in vacuo. The residue was chromatographed on silicagel using 20% EtOAc/hexanes to give the product (1.2 g) in 31% yield.

Part E: The product from Part D was dissolved in dry THF (15 mL) and NaH(60% in oil, 220 mg, 5.5 mmoles) was added. The mixture was stirred at25° C. for 15 min and iodoethane (0.5 mL, 5.7 mmoles) was added. Themixture was stirred at 25° C. for 16 h and then heated to reflux for 2h. The reaction product was then partitioned between EtOAc (100 mL) andH₂O (30 mL). The organic layer was washed with brine, dried and strippedin vacuo. The residue was chromatographed on silica gel using 10%EtOAc/hexanes to give the product (1.1 g). This material was dissolvedin MeOH (20 mL). HCl in ether (3 mL, 1M) was added and the mixture wasstirred at 25° C. for 2 h. Then it was partitioned between EtOAc (100mL) and NaOH (30 mL, 1 M). The EtOAc was washed with brine, dried andstripped in vacuo. The residue was used in the next step withoutpurification.

Part F: The product from Part E (950 mg, 2.4 mmoles) in dry THF (10 mL)was treated with NaH (60% in oil, 140 mg, 3.5 mmoles), stirred at 25° C.for 15 min and 0.25 mL lodoethane (4 mmoles) was added. The resultingmixture was stirred at 25° C. for 16 h and then partitioned betweenEtOAc (100 mL) and H₂O (20 mL). The organic layer was washed with brine,dried and stripped in vacuo. The residue was chromatographed on silicagel using 20% EtOAc/hexanes to give the product (500 mg), which wasconverted into the hydrochloride salt in the usual manner, mp 129-131°C.

EXAMPLE 12N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pymidinamine

Part A: The product from Example 8, Part A (0.2 g) and2-bromo-4-(1-methylethyl)aniline were coupled using the same methoddescribed in Example 8, Part C to provideN-(2-bromo-4-(1-methylethyl)phenyl)-4-methyl-2-pyrimidinamine (0.7 g) asa viscous oil; Mass spec. (NH₃-CI/DDIP): 307 (M+H).

Part B: The product from Part A was alkylated with iodoethane using thesame method described in Example 8, Part D to give the desiredN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine(0.3 g) as the free base.

The hydrochloride salt of this material was prepared in the usualmanner; mp 145-147° C. Mass spec. (NH₃-CI/DDIP). 334 (M+H)⁺.

EXAMPLE 13N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxyethlamino)-2-pyrimidinamine

Part A: A solution of 2,4-dichloro-6-methylpyrimidine (1.0 g) and2-(methylamino)ethanol (0.4 g) in ethanol (50 mL) was refluxed for 24hours. The solvent was evaporated to give a crude residue, which waschromatographed on silica gel using 5% methanol in chloroform to yield2-chloro-4-methyl-6-(N-methyl-2-hydroxyethylamino)pyrimidine (370 mg).

Mass spec. (NH₃-CII/DDIP): 202 (M+H)⁺.

Part B: The hydroxyl group in the product from Part A was protected asthe methoxymethyl ether (MOM-ether) usingN,N-di(1-methylethyl)ethylamine and bromomethyl methyl ether (0.35 g) indry tetrahydrofuran to provide the protected adduct (310 mg, Mass spec.246 (M+H)⁺), which was carried on without purification.

Part C: The protected MOM-ether was coupled with2-bromo-4-(1-methylethyl)aniline using the procedure of Example 8, PartC. Under these conditions, the methoxymethyl protecting group was alsoremoved providingN-(2-bromo-4-(1-methylethyl)phenyl)-4-methyl-6-(N-methyl-2-hydroxyethylamine)-2-pyrimidinamine(mass spec. NH₃-CI/DDIP 379 (M+H)⁺). This hydroxyl group was reprotectedfor subsequent reactions as described in Part B, (Mass spec. forMOM-ether (NH₃-CI/DDIP): 453 (M+H)⁺). Alkylation with iodoethane wascarried out using the method of Example 8, Part D. The MOM-ether wasdeprotected by stirring at room temperature in a solution of methanol (5mL) and hydrochloric acid (1 M, 5 mL) for 24 hours. Upon workup andisolation, the title compound was obtained as the free-base.

The hydrochloride salt was prepared using the described procedure. HighRes. Mass Spec; 407.144640 (M+H)⁺; Expected 407.144648 (M+H)⁺.

EXAMPLE 14N-ethyl-N-(2-iodo4-(1-methylethyl)phenyl)4-thiomorpholino-6-methyl-2-pyrimidinamine,S-oxide

The desired product was obtained by sodium periodate oxidation of theproduct of Example 22, according to the method of J. H. Bushweller et.al. J. Org. Chem. 54:2404, (1989).

EXAMPLE 15N-(2-Bromo-4-(isopropoxy)phenyl)-N-ethyl-4,6dimethyl-2-pymidinamine

Part A: The synthesis of 2-bromo-4-isopropoxy-aniline was accomplishedusing the bromination procedure for 4-isopropoxy-aniline reported byKajigaeshi et al. in Bull. Chem. Soc. Jpn. 61:597-599 (1988). Theaniline, 1 eq. benzyltrimethylammonium tribromide, and 2 eq. calciumcarbonate were stirred at room temperature in a solution of MeOH:CH₂Cl₂(2:5) for one hour. The solids were removed by filtration and thefiltrate was evaporated under vacuum. The residue was taken up in H₂Oand this mixture was then extracted three times with CH₂Cl₂. Thecombined extracts were dried over MgSO₄, filtered, and evaporated undervacuum to give a brown oil, which was purified on silica gel using 15%EtOAc in hexanes. (R_(f)=0.43)

Part B: Using the procedure for Example 1, Parts B-C and substitutingthe aniline from Part A, the title compound was obtained.

EXAMPLE 16N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbonyl)-2-pyrimidinamine

To sodium hydride (60% in oil, 0.24 g, 6.0 mmol) suspended in anhydrousTHF (10 mL) was added morpholine (0.52 g, 6.0 mmol) with stirring; thereaction mixture was warmed to reflux temperature and stirred for 1hour. The reaction mixture was then cooled to ambient temperature and2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-pyrimidine(2.0 g, 5.1 mmol) was added. Stirring was continued for 26 hours. Thereaction mixture was then poured onto a 1N NaOH solution, stirred andextracted three time with EtOAc. The combined organic layers were driedover MgSO₄, filtered and concentrated in vacuo. Column chromatography(Et₂O) afforded the title compound as a solid (900 mg, 39% yield): mp145° C.; NMR (CDCl₃, 300 MHz):d 7.5 (d, 1H, J=1), 7.2 (dd, 1H, J=7,1),7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.3 (m, 11H),3.1-3.0 ( m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H, J=7), 1.15 (t, 3H,J=7); Anal. (C₂₁H₂₇BrN₄O₂) Calcd: C, 56.38; H, 6.08; N, 12.52; Br,17.86; Found: C, 56.07; H, 6.05; N, 12.29; Br, 18.08.

EXAMPLE 17N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylmethyl)-2-pyrmidinamine

A solution ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbonyl)-2-pyrimidinamine(750 mg, 1.72 mmol) in anhydrous THF (1.4 mL) was stirred at ambienttemperature under a nitrogen atmosphere. A solution of borane in THF (1M, 3.6 mL, 3.6 mmol) was added dropaise. The reaction mixture was thenwarmed to reflux temperature and stirred for 20 hours. After cooling toroom temperature, acetic acid (3.5 mL) was added slowly and the mixturewas heated to reflux temperature and stirred for 30 min. After beingcooled to ambient temperature, the reaction mixture was poured onto a 3NNaOH solution, mixed and extracted three times with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered and concentrated invacuo. Column chromatography (EtOAc) of the residue afforded the titlecompound as an oil (300 mg, 39% yield, R_(f) 0.3): NMR (CDCl₃, 300 MHz):d 7.5 (s, 1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 ( s, 1H),4.3-4.1 (m, 1H), 3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H),2.9 (septet, 1H, J=7),2.55-2.35 (br m, 3H), 2.35-2.25 ( m, 2H), 1.3 (d, 6H, J=7), 1.2 (t, 3H,J=7); CI-HRMS: calcd: 433.1603 (M+H), found: 433.1586.

EXAMPLE 18 Methyl2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylate

To sodium hydride (60% in oil, 4.8 g, 120 mmol) in THF (150 mL) atambient temperature under a nitrogen atmosphere was addedmethyl-2-((2-bromo-4-(1-methylethyl)phenyl)amino)-6-methyl-4-pyrimidinecarboxylate(42.8 g, 118 mmol) portionwise over 30 min. After the gas evolutionsubsided, iodoethane (31.2 g, 16 mL, 200 mmol) was added in one portionand the reaction mixture was heated to a gentle reflux for 24 h. Aftercooling to room temperature, the reaction mixture was quenched carefullywith water and extracted three times with ethyl acetate. The combinedorganic extracts were washed with water twice, dried over magnesiumsulfate and filtered. Solvent was removed in vacuo to afford a brownoil. Column chromatography of the oil (Et₂O:hexanes::1:1) provided twofractions: (1)methyl-2-((2-bromo-4-(1-methylethyl)phenyl)amino)-6-methyl-4-pyrimidinecarboxylate(4.6 g, 11% yield, R_(f)=0.8) and (2) the title product (20 g,R_(f)=0.7) as a crude oil. The title product was recrystallized fromhexanes and dried in vacuo to give a solid (18.0 g, 39% yield): mp81-82° C.: NMR(CDCl₃, 300 MHz):d 7.5 (br s, 1H), 7.25 (d, 1H, J=7), 7.15(d, 1H, J=7), 7.1 (s, 1H), 4.3-4.1 (m, 1H), 4.05-3.75 (m, 4H), 2.95(septet, 1H, J=7), 2.3 (br s, 3H), 1.3 (d, 6H, J=7), 1.25 (t, 3H, J=7);CI-HRMS: calcd: 392.0974 (M+H), found: 392.0960.

EXAMPLE 19N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-methylpiperazinylcarbonyl)-2-pyrimidinamine

Using a method analogous to that used for Example 16, but substituting4-methylpiperazine, the desired product was obtained; mp 81-82° C.

EXAMPLE 20N-(2-Bromo-4-(2-hydroxyethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The THP-hydroxyl protecting group was removed using HCl in ether productas described earlier to arrive at the title compound; mp 58-60° C.

EXAMPLE 21N-ethyl-N-(2-methoxy4-(1-methylethyl)phenyl)4,6-dimethyl-2-pyimidinamine

Part A: Using the method of Example 1 and substituting2-amino-5-methylphenol, the intermediate secondary amine was obtained.

Part B: By double methylating the amino and the phenol groups usingexcess sodium hydride and iodomethane in THF, the desired product wasobtained.

EXAMPLE 22N-ethyl-N-(2-iodo4-(1-methylethyl)phenyl)4-thiomorpholino-6-methyl-2-pyrimidinamine

Using the iodination method of Example 11 and the general synthesisdescribed in Example 4 the desired compound was obtained; mp 51-53° C.

EXAMPLE 23N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-amine

Part A: Methyl magnesium bromide (300 mmole, 3M in ether, Aldrich) wasadded dropwise over a 10 min period to a solution of cyanuric chloride(12.9 g, 69.9 mmole) in CH₂Cl₂ (300 mL) under N₂ at −20° C. and stirringwas continued at −20° C. for 4.5 hours. Water (36 mL) was added dropwisewhile keeping the reaction temperature below −15° C. The reactionmixture was allowed to reach room temperature and magnesium sulfate (40g) was added. It was let stand for one hour. The reaction mixture wasfiltered and the solvent removed leaving a yellow solid (11.06 g). Thismaterial was purified using flash chromatography (CH₂Cl₂, silica) andgave 2,4-dichloro-6-methyl-s-triazine as a white solid (7.44 g) in 65%yield.

Part B: 2,4-dichloro-6-methyl-s-triazine (3 g, 18.29 mmol),2-bromo-N-ethyl-4-isopropylaniline (6.07 g, 25.07 mmol) anddiisopropylethylamine (3.2 g, 25.07 mmol) in dioxane (60 mL) under N₂were heated at reflux for three hours. The solvent was removed and theresidue was purified using flash chromatography (CH₂Cl₂, silica) toprovide the product (4.58 g) as a clear oil in 68% yield.

Part C: The product from Part B (500 mg, 1.35 mmol) was dissolved indioxane (20 mL) under N₂ at room temperature and morpholine (247 mg,2.84 mmol) was added in one portion. Stirring was continued at roomtemperature for 17 hours. The reaction solvent was stripped away and theresidue was triturated with ethyl acetate/hexane (1:3). The trituratedmaterial was purified using flash chromatography (EtOAc/hexane, 1:3Silica). The product was collected as a clear oil (550 mg) in 97% yield.C₁₉H₂₆N₃OBr

EXAMPLE 24 N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(hydroxymethyl)-2-pyrimidinamine

The product of Example 18 and lithium borohydride (1.5 eq.) were stirredin dry THF under nitrogen for fifty hours. The reaction was then pouredinto water and extracted three times with CHCl₃. The combined extractswere dried over MgSO₄, filtered, and evaporated under vacuum to give anearly quantitative yield of the product as a light yellow oil.

EXAMPLE 25N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methoxymethyl)-2-pyrimidinamine

To the product of Example 24 and sodium hydride (1.1 eq.) in dry THFunder nitrogen was added iodomethane (1.1 eq.) and after four hours thereaction was poured into H₂O and extracted three times with CHCl₃. Thecombined extracts were dried over MgSO₄, filtered, and evaporated undervacuum. The material was purified by chromatography on silica gel using10% EtOAc in hexanes to give a light yellow oil. (R_(f)=0.37)

Example 26N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine

Part A: 2-Bromo-4-isopropylaniline (8.9 g, 42 mmol) and6-hydroxy-4-methyl-2-thiomethylpyrimidine (5 g, 32 mmol) were combinedunder N₂ and heated at 190° C. for 8 hours. The reaction mixture wascooled to room temperature. The residue was purified using flashchromatography (CH₂Cl₂/MeOH, 25:1, silica) to provide 9.16 g (89% yield)white solid.

Part B: The product from Part A (6 g, 18.6 mmol) and phosphorusoxychloride (20 mL, 214 mmol) were refluxed under N₂ for 15 minutes. Thereaction mixture was cooled to room temperature, slowly poured onto ice(200 g), stirred about 30 minutes until the ice had melted, and theaqueous mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic extracts were treated with water (100 mL) and brine(100 mL), dried over anhydrous sodium sulfate, filtered and strippedleaving 6.1 g tan oil. This material was purified using flashchromatography (CH₂Cl₂/hexane, 1:1, silica) to give 4.48 g (70% yield)of clear oil.

Part C: To the product of Part B (4.3 g, 12.65 mmol) indimethylformamide (30 mL) under N₂ was added sodium hydride (658 mg,16.45 mmol, 60% dispersion in oil) was added in small portions. Afteraddition was complete, stirring was continued 4 hours at roomtemperature. Water (100 mL) was added to the reaction mixture and it wasextracted with ethyl acetate (3×100 mL). The combined organic extractswere treated with water (100 mL) and brine (100 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered and stripped leaving4.8 g tan oil. This material was purified using flash chromatography(EtOAc/hexane, 1:6, silica gel) to afford 4.4 g (95% yield) of oil.

Part D: The product of Part C (2 g, 5.4 mmol) and sodium thiomethoxide(558 mg, 7.6 mmol) in dioxane (50 mL) under N₂ were heated to reflux (20hrs.). The solvent was stripped and the residue was purified using flashchromatography (CH₂Cl₂/hexane, 1:1, silica) to give 1.86 g (91% yield)of clear oil. Analysis: MS (NH3—CI/DDIP) : 380 (M+H)⁺.

EXAMPLE 27N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine,dioxide

To the product of example 26 (1.8 g=4.8 mmol) in CH₂Cl₂ (100 mL) underN₂ was added 3-chloroperbenzoic acid (3.16 g, 14.67 mmol, 80-85% purity)in small portions and after addition, stirring was continued for 30minutes. Unreacted peroxide was consumed using 10% sodium sulfite (5mL), and the reaction mixture was diluted with CH₂Cl₂ (150 mL) followedby washing with 5% sodium bicarbonate (100 mL) and brine (100 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andstripped leaving 2.19 g yellow oil. This material was purified usingflash chromatography (CH₂Cl₂, silica) to provide 1.6 g of oil (79%yield). MS (NH3-CI/DDIP): 412 (M+H)⁺.

EXAMPLE 28N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine,S-oxide

To Example 26 product (770 mg, 2 mmol) in methanol (200 mL) was addedsodium periodate (648 mg, 3 mmol) in water (10 mL) in one portion andthe reaction mixture was refluxed 28 hours. The reaction solvent wasstripped away and the residue was partitioned between ethyl acetate (200mL) and water (50 mL). The organic layer was separated and treated withbrine (50 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and stripped leaving 820 mg tan residue. This materialwas purified using flash chromatography (EtOAc/hexane, 1:1, silica) toafford 570 mg (71% yield) of oil. MS (NH3-CI/DDIP) : 396 (M+H)⁺.

EXAMPLE 29N-[2-bromo-4(1-methylethyl)phenyl]-N-ethyl-4-methyl-6-benzyloxy-1,3,5triazin-2-amine

Benzyl alcohol (197 mg, 1.82 mmol, 1.2 eq) was added slowly to asolution of NaH (73 mg 60% dispersion, 1.82 mmol) in dry DMF and stirredat room temperature for 15 minutes. The product from Part B (560 mg,1.52 mmol) was then added and the resulting mixture stirred at roomtemperature for 2 hours, The reaction mixture was then poured into waterand extracted three times with ethyl acetate. The organic layer wasdried over magnesium sulfate, filtered and concentrated in vacuo. Thecrude oil was chromatographed on silica using 20% ethyl acetate inhexanes as solvent to afford the title compound. C₂₂H₂₅N₄OBr Calcd: C,55.46; H, 5.46; N, 11.76; Found: C, 55.30; H, 5.41; N, 12.02.

EXAMPLE 30N-[2-iodo-4-dimethylhydroxymethylphenyl]-N-ethyl-4-6-dichloro-1,3,5triazin-2-amine

Part A: Ethyl 4-aminobenzoate (5.0 gr, 30.27 mmol) and sodiumbicarbonate (3.81 g, 45.40 mmol, 1.5 eq.) were added to a 50:50 mixtureof methylene chloride and water. The mixture was chilled to 0 degreesand I₂, (11.53 g, 45.40 mmol, 1.5 eq.) was added slowly. The reactionmixture was allowed to come to room temperature and was stirred for 72hours. The layers were then separated and the aqueous layer washed withmethylene chloride. All organics were combined and dried over magnesiumsulfate, filtered and concentrated in vacuo. The resulting oil waschromatographed on silica using 30% ethyl acetate in hexanes as solventto afford ethyl 3-iodo-4-aminobenzoate. C₉H₁₀NO₂I MS 292 (M+H)⁺ 309(M+NH₄)⁺.

Part B: The product from part A (1.0 g, 3.4 mmol) was added to astirring solution of NaH (0.21 gr, 5.2 mmol) in 25 mL of dry DMF andallowed to stir at room temperature for 10 minutes. Ethyl iodide (0.8 g,5.2 mmol) was then added and the mixture was allow to stir for 24 hours.The reaction was then poured into water and extracted with ethylacetate. The organic layer was dried with magnesium sulfate, filtered,and concentrated in vacuo. The crude material was chromatographed onsilica using 30% ethyl vacuo. The crude material was chromatographed onsilica using 30% ethyl acetate in hexanes as solvent to afford ethyl3-iodo-4-(N-ethyl)aminobenzoate. C₁₁H₁₄NO₂I MS 320(M+H)⁺.

Part C: The product from part B (0.32 g, 1.0 mmol) was dissolved indioxane and cyanuric chloride (0.18 g, 1.0 mmol) was added slowly. Thereaction was heated to reflux for 4 hours, stirred at room temperaturefor 24 hours, then poured into water and extracted with ethyl acetate.The organic layer was dried with magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was chromatographed on silicausing 10% ethyl vacuo. The crude material was chromatographed on silicausing 10% ethyl acetate in hexanes as solvent to affordN-[2-iodo-4-ethylcarboylate]-N-ethyl-4-6-dichloro-1,3,5triazin-2-amine.C₁₄H₁₃N₄O₂C₂I MS 467 (M+H)⁺.

Part D: The product of part C (0.26 g, 0.6 mmol) was dissolved in 20 mLmethylene chloride and chilled to −20 degrees. Methyl magnesium slowly.The reaction was allowed to come to room temperature and stirred for 4hours, then poured into water and the layers were separated. The aqueouslayer was extracted with methylene chloride and the organic layerscombined, dried with magnesium sulfate, filtered, and concentrated invacuo. The crude material was chromatographed on silica gel using 30%ethyl acetate in hexanes as solvent to afford the title compound.C₁₅H₁₈N₄OICl MS 453 (M +H)⁺.

EXAMPLE 31

N-(2-iodo4-(1-methylethyl)phenyl)-N-allyl4-morpholino-6-methyl-2-pyrimidinamine

mp 109-112° C. Elemental analysis for C₂₁H₂₇N₄IO HCl: Theory C, 48.99;H, 5.48; N, 10.88; I, 24.65; Cl, 6.89. Found C, 48.81; H, 5.43; N,10.59, I, 24.67; Cl, 6.86.

EXAMPLE 32N-(2-iodo4-(1-methylethyl)phenyl)-N-ethyl-4-chloro-6-methyl-2-pyrimidinamine

Guanidine 39.5 mmoles crude, obtained by treatment of the correspondingguanidinium salt with K₂CO₃, 15 mL (118 mmoles) ethyl acetoacetate and2.0 g (14.47 mmoles) K₂CO₃ were heated to reflux in 120 mL absoluteethanol for 100 hr. Then the solvent was stripped in vacuo and theresidue was chromatographed on silica gel using 40% EtOAc/hexanes aseluent to give 4 g product, a 27% yield for the three steps.

The 4-hydroxypyrimidine obtained from the above reaction (2.47 g, 6.69mmoles) was dissolved into 20 mL POCl₃ and stirred at 25° C. for 4 hr.The reaction mixture was poured into ice, stirred for 30 min, andextracted with 100 mL EtOAc. The EtOAc extract was washed with brine,dried and stripped in vacuo. The residue was chromatographed on silicagel using 20% EtOAc/hexanes to give 1.64 g of the corresponding4-chloropyrimidine (63% yield).

1.6 g (4.13 mmoles) 4-chloropyrimidine obtained above, and 0.33 g (8.25mmoles) of NaH (60% in oil) in 10 mL dry DMF at 25° C. were stirredtogether for 15 min. Then 0.7 mL (8.75 mmoles) of EtI was added and thereaction was stirred at 0° C. for 2 h and at 25° C. for 16 h. It wasthen partitioned between 100 mL EtOAc and 25 mL water and the EtOAc waswashed with water (2×30 mL), brine, dried and stripped in vacuo. Theresidue was chromatographed on silica gel using 8% EtOAc/hexanes to give1.2 g product as a viscous liquid (70% yield); elemental analysis forC₁₆H₁₉N₃ClI: Theory: C, 46.23; H, 4.61; N, 10.11; Cl, 8.53; I, 30.53.Found: C, 46.36; H, 4.57; N, 9.89; Cl, 8.79; I, 30.38.

EXAMPLE 33N-(2-methylthio4-(1-methylethyl)phenyl)-N-ethyl-4(S)-(N-methyl-2′-pyrrolidinomethoxy)-6-methyl-2-pyrimidinamine

The chloropyrimidine described above, 0.66 g (1.59 mmoles), 70 mg (1.76mmoles) of NaH (60% in oil) and 0.19 mL (1.6 mmoles)(S)-N-methylprolinol in 10 mL of dry THF under nitrogen were stirred at25° C. for 36 h and then refluxed for 2h. The mixture was partitionedbetween 10 mL EtOAc and 20 mL water and the EtOAc was washed with water,brine, dried and stripped in vacuo. The residue was chromatographed onsilica gel using 0.5% NH₄OH/5% CH₃OH/CH₂Cl₂ as eluent to give 340 mgproduct, which was converted into the dihydrochloride salt by treatmentwith 1 M HCl in ether, mp 101-103° C. (dec). Elemental analysis forC₂₂H₃₁N₄IO. 2HCl: Theory C, 46.57; H, 5.86; N, 9.88; Cl, 12.50. Found C,46.69; H, 6.02; N, 9.45; Cl, 12.69.

EXAMPLE 34N-(2,6-dibromo-4-(1-methylethyl)phenyl)4-thiomorpholino-6-methyl-2-pyrimidinamine

580 mg (2.46 mmoles) of 2-chloro-4-thiomorpholino-6-methylpyrimidine,793 mg (2.7 mmoles) of2,6-dibromo-4-isopropylaniline and 216 mg (5.4mmoles) of NaH (60% in oil) were refluxed in toluene for 6 hr andpurified by silica gel chromatography using 25% EtOAc/hexanes (79%yield); mp 194-195° C. Elemental analysis for C₁₈H₂₂N₄Br₂S: Theory C,44.46; H, 4.56; N, 11.52; Br: 32.87; S,6.59. Found: C, 44.67; H, 4.54;N, 11.24; Br: 32.8; S, 6.62.

EXAMPLE 35N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The product was synthesized by lithium-bromine exchange of theappropriately substituted 2-bromo-4-isopropylanilinopyrimidine withnBuLi in THF at 0° C. followed by reaction with dimethyldisulfide. Itwas purified by silica gel chromatography using 8% EtOAc/hexanes aseluent, (37% yield); mp 64-66° C. Elemental analysis for C₁₈H25N₃S: C,68.53; H, 7.99; N, 13.32; S, 10.16. Found: C, 68.43; H, 7.94; N, 13.16;S, 10.02.

EXAMPLE 36N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6dimethyl-2-pyrimidinamine

The hydrochloride salt of Example 35, was formed in the usual manner; mp141-142° C. Elemental analysis for C₁₈H₂₅N₃S HCl: Theory C, 61.43; H,7.45; N, 11.94; S, 9.11; Cl, 10.07. Found: C, 61.07; H, 7.40; N, 11.80;S, 9.37; Cl, 9.77.

EXAMPLE 37N-(2-methylsulfinyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The sulfide of Example 35, (300 mg, 0.95 mmoles), was reacted with 300mg (1.41 mmoles) NaIO₄ in 6 mL MeOH and 3 mL water at 25° C. for 24 h.The reaction mixture was partitioned between 100 mL EtOAc and 25 mLwater and the EtOAc extract was washed with water, brine, dried andstripped in vacuo. The residue was purified by silica gel chromatographyusing 1:1 EtOAc/hexanes as eluent to give 220 mg product, (70% yield);mp 144-146° C. Elemental analysis for C₁₈H₂₅N₃O₅: Theory C, 65.22; H,7.60; N, 12.68; S, 9.67. Found: C, 65.12; H, 7.63; N, 12.48; S, 9.71.

EXAMPLE 38N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiazolidino-6-methyl-2-pyrimidinamine

The title compound was obtained as a viscous liquid. Elemental analysisfor C₁₉H₂₅N₄IS: Theory C, 48.72; H, 5.38; N, 11.96; S, 6.84; I, 27.09.Found: C, 48.80; H, 5.36; N, 11.84; S, 6.95; I, 27.05.

EXAMPLE 39N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was obtained as a viscous liquid. Elemental analysisfor C₁₆H₂₀N₃IO: Theory C, 48.37; H, 5.08; N, 10,58. Found C, 48.27; H,5.00; N, 10.07.

EXAMPLE 40N-(4,6-dimethyl-2-pyrimidinamino)-2,3,4,5-tetrahydro-4-(1-methylethyl)-1,5-benzothiazepine

To 4 grams, (15.32 mmoles) of 2-iodo-4-isopropylaniline, and 2.53 g(18.4 mmoles) of 4,6-dimethyl-2-mercaptopyrimidine in 30 mL DMF, wereadded 4.8 g (34.4 mmoles) of K₂CO₃ and 600 mg (9.2 mmoles) of Cu powderand the resulting mixture was heated to reflux for 2 h. After cooling,30 mL EtOAc was added and the solids were filtered off. The filtrate waspartitioned between 200 mL EtOAc and 50 mL water and the EtOAc layer waswashed with water (3×60 mL), brine, dried and stripped in vacuo toprovide an oily residue that was used without further purification;MS(m/e) 275 (M+2, 20%); 274 (M+1, 100%).

To 0.6 g (2.2 mmoles) of the above crude product in 8 mL dry xylenes wasadded 132 mg (3.3 mmoles) NaH (60% in oil) and the mixture was heated toreflux for 5 h. Then 0.22 mL (2.2 mmoles) of 1,3-dibromopropane wasadded and the reaction was heated for another 2 h. Another 60 mg (1.2mmoles) NaH (60% in oil) was added and heating was continued for another3 h. After cooling the solids were filtered off, the solvent removed invacuo, and the filtrate chromatographed on silica gel using 8%EtOAc/hexanes to give 220 mg product (32% yield for the two steps); Highres MS: calc 314.169095; measured: 314.168333. This was converted intothe hydrochloride salt by treatment with 1M HCl in ether, mp 157-159° C.

EXAMPLE 41N-(2-methylsulfonyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The sulfoxide of Example 37, (100 mg, 0.3 mmoles) was stirred in 4 mL ofCH₂Cl₂ and 8 mL water with 20 mg (0.09 mmole) of benzyltriethylammoniumchloride and 94.5 mg (0.6 mmole) KMnO₄ at 25° C. for 16 h. The mixturewas partitioned between 60 mL EtOAc and 40 mL water and the EtOAc waswashed with water, brine, dried and stripped in vacuo. The residue waspurified by silica gel chromatography using 25% EtOAc/hexanes to give 85mg product (81% yield); mp 174-175.3° C. Elemental analysis forC₁₈H₂₅N₃O₂S: Theory C, 62.22; H, 7.25; N, 12.09; S, 9.23. Found: C,62.13; H, 7.28; N, 11.93; S, 9.12.

EXAMPLE 42N-(2-ethylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6dimethyl-2-pyrimidinamine

The title compound was prepared in the same manner as the product ofExample 36; mp 128-130° C. Elemental analysis for C₁₉H₂₇N₃S HCl: TheoryC, 62.36; H, 7.71; N, 11.48; S, 8.76; Cl, 9.69. Found: C, 62.64; H,7.75; N, 11.43; S, 8.59; Cl, 9.58.

EXAMPLE 43N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in the same manner as the product ofExample 44; mp 77-78° C. Elemental analysis for C₁₉H₂₆N₄OS: Theory C,63.66; H, 7.31; N, 15.63; S, 8.95. Found C, 63.70; H, 7.32; N, 15.64; S,8.94.

EXAMPLE 44N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

To 4 g (29.6 mmoles) of 4′-aminoacetophenone in 20 mL CH₂Cl₂ and 50 mLwater containing 3.6 g (42 mmoles) NaHCO₃ was added 9.0 g (35.4 mmoles)of I₂. The mixture was stirred at 25° C. for 20 h. Then 20 mL ofsaturated aqueous Na₂SO₃ was added and the mixture was stirred for 10min and partitioned between 120 mL EtOAc and 10 mL water. The EtOAcextract was washed with brine, dried and stripped in vacuo and theresidue chromatographed on silica gel using 25% EtOAc/hexanes as eluentto give 6.1 g product (79% yield).

To 3.05 g (11.69 mmoles) of 4′-amino-3′-iodoacetophenone in a mixture of40 mL ethanol and 10 mL 3M NaOH was added 2.10 g (25.20 mmoles)methoxyamine hydrochloride and the mixture was heated to reflux for 2 h.The ethanol was stripped off in vacuo, the residue was partitionedbetween 100 mL EtOAc and 30 mL water and the EtOAc was washed withwater, brine, dried and stripped in vacuo. The residue waschromatographed on silica gel using 20% EtOAc/hexanes to give 2.8 gproduct (83% yield).

The above product 1.5 g (5.18 mmoles) was coupled with4,6-dimethyl-2-mercaptopyrimidine as described above, to give thecorresponding adduct in 70% yield, after chromatographic purification.

The above product, 1.1 g (3.64 mmoles) was treated with 190 mg (4.73mmoles) NaH (60% in oil) in 7 mL dry xylenes at reflux for 5.5 hours.The reaction mixture was then partitioned between 100 mL EtOAc and 20 mLwater and the EtOAc was washed with water, brine, dried and stripped invacuo. The residue was purified by silica gel chromatography using 25%EtOAc/hexanes to give 900 mg product (82% yield).

The above product, 900 mg (2.98 mmoles) was treated with 470 mg (3.4mmoles) K₂CO₃ and 0.22 mL (3.54 mmoles) CH₃I at 25° C. for 4 h. Then itwas partitioned between 100 mL EtOAc and 20 mL water, the EtOAc waswashed with brine, dried and stripped in vacuo. The residue was used forthe next reaction without further purification.

The above product, 940 mg (2.97 mmoles) was treated with 160 mg (4.0mmoles) NaH (60% in oil) in 7 mL dry DMF for 20 min at 25° C. and then0.32 mL (4.0 mmoles) EtI was added. The mixture was stirred at 25° C.for 16 h and partitioned between 100 mL EtOAc and 20 mL water, the EtOAcwas washed with brine, dried, stripped in vacuo and the residue waschromatographed on silica gel using 20% EtOAc/hexanes to give 600 mgproduct (58% yield); mp 106-108° C. Elemental analysis for C₁₈H₂₄N₄OS:Theory C, 62.76; H, 7.02; N, 16.27; S, 9.31. Found C, 62.75; H, 7.03; N,16.12; S, 9.45.

EXAMPLE 45N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The sulfide obtained from the sequence described above (0.3 g, 0.87mmoles) was dissolved in 10 mL CH₂Cl₂ and 0.53 g (2.61 mmoles) ofm-chloroperbenzoic acid (mCPBA 85%) was added and the mixture wasstirred at 25° C. for 16 min. The reaction mixture was quenched withNa₂SO₃ and partitioned between 40 mL CH₂Cl₂ and 30 mL 5% NaHCO₃. Theorganic layer was dried, stripped in vacuo and the residue waschromatographed on silica gel using 40% EtOAc/hexanes to give 430 mgproduct, a 40% yield, mp 151-154° C. Elemental analysis for C₁₈H₂₄N₄O₃S:Theory C, 57.43; H, 6.43; N, 14.88; S, 8.52. Found: C, 57.24; H, 6.40;N, 14.18; S, 8.60.

EXAMPLE 46N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

2-Iodo-4-bromoaniline was coupled with 4,6-dimethyl-2-mercaptopyrimidinein 93% yield. One gram of the adduct (3.22 mmoles) was dissolved in 10mL methanol and 4 mL (4 mmoles) 1 M HCl in ether was added. The mixturewas stirred at 25° C. for 2 h, the solvent was stripped in vacuo and theresidue was partitioned between 150 mL of an 1:1 mixture EtOAc andCH₂Cl₂ and 80 mL satd. NaHCO₃. The organic layer was dried and strippedin vacuo to give 900 mg of the disulfide product, which was dissolved in10 mL absolute ethanol and cooled to 0° C. To that solution 110 mg (2.92mmoles) of NaBH₄ was added and the mixture was allowed to warm to 25° C.and stirred for 20 min before 0.36 mL (5.76 mmoles) CH₃I was added andthe mixture was stirred at 25° C. for 2 h. The solvent was stripped invacuo and the residue was partitioned between 100 mL EtOAc and 30 mLsatd. NaHCO₃. The EtOAc was washed with brine, dried and stripped invacuo. The residue was chromatographed on silica gel using 20%EtOAc/hexanes to give 840 mg product, 80% yield for the two steps.MS(m/e): 326 (M+3, 100%); 324 (M+1, 93%).

This was ethylated under the conditions described above in 90% yield,mp91-93° C. Elemental analysis for C₁₅H₁₈BrN₃S: Theory C,51.15; H, 5.15;N, 11.93; Br, 22.68; S, 9.10. Found C, 51.25; H, 5.15; N, 11.89; Br,22.42; S, 9.22.

EXAMPLE 47N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in a manner similar to the product ofExample 46; mp 85-87° C. Elemental analysis for C₁₈H₂₅N₃S: Theory C,68.53; H, 7.99; N, 13.32; S, 10.16. Found: C, 68.56; H, 8.08; N, 13.24;S, 10.27.

EXAMPLE 48N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in a manner similar to the product ofExample 46; mp 140-141° C. Elemental analysis for C₁₇H₂₃N₃S.HCl: TheoryC, 60.43; H, 7.16; N, 12.44; S, 9.49; Cl, 10.49. Found C, 60.42; H,6.89; N, 12.36; S, 9.61; Cl, 10.63.

EXAMPLE 49N-(2-methylthio-4-(N-acetyl-N-methylamino)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in a manner similar to the product ofExample 46; mp 158-160° C. Elemental analysis for C₁₈H₂₄N₄OS: Theory C,62.76; H, 7.02; N, 16.26; S, 9.31. Found C, 62.67; H, 7.07; N, 16.24; S,9.56.

EXAMPLE 50N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in a manner similar to the product ofExample 46; mp 99-100° C. Elemental analysis for C₁₈H₂₃N₃O₂S: Theory C,62.58; H, 6.71; N, 12.16; S, 9.28. Found C, 62.83; H, 6.78; N, 12.08; S,9.44.

EXAMPLE 51N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

A mixture of 352 mg (1 mmole) 4-bromo-2-methylmercaptoanilinopyrimidine,14.3 mg (0.1 mmole) CuBr and 0.5 mL (2.5 mmoles) 25% w/w MeONa in MeOHwas heated to reflux in 5 mL dry DMF for 1.5 h. The reaction mixture waspartitioned between 100 mL EtOAc and 30 mL water and the EtOAc layer waswashed with water (2×30 mL), brine, dried and stripped in vacuo. Theresidue was chromatographed on silica gel using 20% EtOAc/hexanes togive 210 mg product (69% yield); mp 128-130° C. Elemental analysis forC₁₆H₂₁N₃OS.¼H₂O: Theory C, 62.41; H, 7.07; N, 13.64; S, 10.41. Found C,62.06; H, 6.97; N, 13.26; S, 10.47.

EXAMPLE 52N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in a manner similar to the product ofExample 51; mp 112-113° C. Elemental analysis for C₁₆H₁₈N₄S: Theory C,64.40; H, 6.08; N, 18.78; S, 10.74. Found: C, 64.28; H, 6.16 N, 18.58;S, 11.08.

EXAMPLE 53N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

To 0.5 g (1.68 mmoles) of the nitrile of Example 52 in 10 mL dry C₆H₆was added 1.1 mL (3.3 mmoles) of a 3 M solution CH₃MgI in ether and themixture was stirred at 25° C. for 2 h and at reflux for 1 h. Thereaction was quenched with water and 10% HCl and stirred for 20 minbefore 1 M NaOH was added until the solution was alkaline and themixture was extracted with 100 mL EtOAc. The organic layer was washedwith water, brine, dried and stripped in vacuo. The residue waschromatographed on silica gel using 20% EtOAc/hexanes to give 370 mgproduct (70% yield); mp 125-126° C. Elemental analysis for C₁₇H₂₁N₃OS:Theory C, 64.73; H, 6.71; N, 13.32; S, 10.16. Found C, 64.53; H, 6.73;N, 13.08; S, 10.19.

EXAMPLE 54N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

The title compound was prepared in a manner similar to the product ofExample 53; mp 139-141° C. Elemental analysis for C₁₈H₂₃N₃OS: Theory C,65.62; H, 7.04; N, 12.75; S, 9.73. Found C, 65.33; H, 7.19; N, 12.51; S,9.62.

EXAMPLE 55N-(4-(1-methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

To 1.05 g (3.33 mmoles) of the ketone of Example 53 in 20 mL absoluteethanol cooled to 0° C. was added 127 mg (3.32 mmoles) NaBH₄ and themixture was allowed to warm to 25° C. and stirred for 16 h. Then thesolvent was stripped in vacuo and the residue was partitioned between100 mL EtOAc and 30 mL 0.3 M NaOH. The EtOAc was washed with water,brine, dried and stripped in vacuo. The residue was chromatographed onsilica gel using 2:1 EtOAc/hexanes to give 1 g product; mp 46-49° C. Theabove alcohol, 0.72 g (2.27 mmoles), was reacted with 108.09 mg (2.7mmoles) of NaH (60% in oil) in 5 mL dry DMF at 25° C. for 20 min andthen 0.3 mL (4.8 mmoles) of CH₃I was added. The mixture was stirred for20 h and an additional 60 mg (1.5 mmoles) of NaH (60%) was added, aswell as 0.1 mL CH₃I and the mixture was stirred for an additional 16 h.It was then partitioned between 100 mL EtOAc and 30 mL water and theEtOAc was washed with water (2×30 mL), brine, dried and stripped invacuo. The residue was chromatographed on silica gel using 20%EtOAc/hexanes to give 600 mg product as a viscous liquid. This wasconverted into the hydrochloride salt by treatment with 1 M HCl inether, mp 120-122° C.

EXAMPLE 56N-(4-(N-methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

A solution of 0.2 g (0.58 mmole)4-N-acetyl-N-methyl-2-methylmercaptoanilinopyrimidine, in 10 mL ethanoland 2 mL water containing 272 mg (5 mmoles) KOH was refluxed for 4 h. Anadditional 200 mg of KOH was added and the heating was continued for 3h. The ethanol was stripped in vacuo and the residue was partitionedbetween 100 mL EtOAc and 30 mL water. The EtOAc extract was washed withbrine, dried and stripped in vacuo. The residue was chromatographed onsilica gel using 1:1 EtOAc/hexanes to give 140 mg product, an 80% yield,mp 141-142° C. Elemental analysis for C₁₆H₂₂N₄S: Theory C, 63.54; H,7.33; N, 18.52; S, 10.60. Found C, 63.63; H, 7.41; N, 18.55; S, 10.80.

EXAMPLE 57N-(4-(N,N-dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

To 0.36 g (1.2 mmoles) 4-N-methyl-2-methylmercaptoanilinopyrimidine in 4mL dry DMF was added 60 mg (1.5 mmoles) NaH (60% in oil) and the mixturewas stirred for 20 min before 0.1 mL (1.67 mmoles) CH₃I was added andthe reaction was continued at 25° C. for 16 h. It was then partitionedbetween 100 mL EtOAc and 20 mL water. The EtOAc extract was washed withwater, brine, dried and stripped in vacuo. The residue waschromatographed on silica gel using 20% EtOAc/hexanes to give 150 mgproduct (40% yield); mp 119-120° C. Elemental analysis for C₁₇H₂₄N₄S:Theory C, 64.52; H, 7.64; N, 17.70; S, 10.13. Found C, 64.55; H, 7.65;N, 17.50; S, 10.31.

EXAMPLE 58N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-formyl-6-methyl-2-pyrimidinamine

Example 23 product (453 mg, 1.2 mmol) and manganese dioxide (1.7g, 20mmol) were heated to reflux in 25 mL dichloromethane for three days. Thereaction was filtered through a pad of Celite, and the filtrate wasconcentrated in vacuo to give a light yellow oil. The oil was purifiedby silica gel chromatography using 10% ethyl acetate in hexanes to yield112 mg of a white solid. CI-HRMS: calcd: 362.0868 (M+H), found:362.0864.

EXAMPLE 59N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6-methyl-2-pyrimidinamine

Compound XLVII from Scheme 12 above (0.41 g, 0.92 mmol) and sodiumborohydride (76 mg, 2 mmol) in 10 mL ethanol were stirred for 21 hoursat room temperature. The reaction was acidified with 1.0 N hydrochloricacid, stirred for ten minutes, basified with 1.0 N sodium hydroxide andextracted with dichloromethane. The combined extracts were dried withmagnesium sulfate and stripped in vacuo to yield a clear oil which waschromatographed on silica gel using 30% ethyl acetate in hexanes to give345 mg product (92% yield). CI-HRMS: calcd: 408.1287 (M+H), found:408.1284.

EXAMPLE 60N-(2-Bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

N-(2-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine(214 mg, 0.58 mmol) in 15 mL dichloromethane under nitrogen was cooledin a dry ice/acetone bath, and boron tribromide (1.0 M indichloromethane, 0.58 mL) was slowly added. The reaction was allowedgradually to warm to room temperature whereupon it was stirredovernight. After quenching with water, the aqueous portion was basifiedwith saturated sodium bicarbonate and extracted with dichloromethane.The combined extracts were dried with magnesium sulfate and concentratedin vacuo to give a tan solid. The solid was recrystallized from ethylacetate/hexanes to yield 58 mg product; mp 157-160° C. Anal. Calcd: %C,51.15; %H, 5.15; %N, 11.93; %Br, 22.69. Found: %C, 51.02; %H, 5.10; %N,11.83; %Br, 22.52.

EXAMPLE 61N-(3-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

Part A (Synthesis of 3-bromo-4,6-dimethoxy aniline): To a mixture of2,4-dimethoxy aniline (5.0 g, 33 mmol) and potassium carbonate (10.4 g,75 mmol) in 30 mL chloroform was slowly added bromine (5.27 g, 33 mmol)in 20 mL chloroform. After stirring two hours the reaction was washedthree times with water, dried with magnesium sulfate, and concentratedin vacuo to give a dark solid. The material was purified bychromatography on silica gel using 20% ethyl acetate in hexanes to yield1.77 g product as a tan solid (23% yield).

Part B: Using the procedure for Example 1; Parts B-C and substitutingthe aniline from Part A above, the title compound was obtained.

EXAMPLE 62N-(2,3-Dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

Part A (Synthesis of 2,3dibromo-4,6-dimethoxy aniline): 2,4-dimethoxyaniline, 1 eq. benzyltrimethylammonium tribromide, and 2 eq. calciumcarbonate were stirred at room temperature in a solution ofmethanol:dichloromethane (2:5) for one hour. The solution was filtered,the filtrate was evaporated under vacuum, and the residue taken up inwater and extracted three times with dichloromethane. The combinedextracts were dried over magnesium sulfate, filtered, and evaporatedunder vacuum to give a brown oil, which was purified on silica gel using20% ethyl acetate in hexanes. (Rf=0.2)

Part B: Using the procedure for Example 1; Parts B-C and substitutingthe aniline from Part A above, the title compound was obtained.

EXAMPLE 63N-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine

Part A: The synthesis of 2,6-dibromo-4-ethoxy-aniline was accomplishedusing the bromination procedure for 4-ethoxy-aniline reported byKajigaeshi et. al. in Bull. Chem. Soc. Jpn. 61:597-599 (1988). Theaniline, 1 eq. benzyltrimethylammonium tribromide, and 2 eq. calciumcarbonate were stirred at room temperature in a solution of MeOH:CH₂Cl₂(2:5) for one hour. The solids were collected, the filtrate wasevaporated under vacuum, and the residue taken up in H₂O and extractedthree times with CH₂Cl₂. The combined extracts were dried over MgSO₄,filtered, and evaporated under vacuum to give a brown oil, which waspurified on silica gel using 10% EtOAc in hexanes.

Part B: Using the procedure for Example 1; Parts B-C and substitutingthe aniline from Part A above, the title compound was obtained.

EXAMPLE 641-(2-Bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole

Part A: A solution of 42.80 g (0.200 mole) of the potassium salt offormyl-succinonitrile (K. Gewald, Z. Chem., 1:349 (1961)) and 29.20 g(0.200 mole) of 2-bromo-4-isopropylaniline in a mixture of 50 mL ofglacial acetic acid and 120 mL of ethanol was refluxed (nitrogenatmosphere) for two hours. The mixture was stripped of most of theacetic acid and ethanol and the residue was taken up in ethyl acetate.This solution was washed with 10% sodium bicarbonate solution, driedwith anhydrous sodium sulfate, and evaporated to give a dark, oilyresidue, which was chromatographed on silica gel with 80:20 hexane-ethylacetate to give 24.23 g (40%) ofN-(2-bromo-4-isopropylphenyl)-aminomethylene-succinonitrile. Mass spec:(m+NH₄)⁺=321.0; calculated, 321.0.

Part B: To a solution of 10 mL of 1M potassium tert-butoxide intetrahydrofuran and 10 mL of ethanol was added 1.11 g (3.65 mmole) ofN-(2-bromo-4-isopropyl-phenyl)-aminomethylene-succinonitrile (Part A).The mixture was stirred for 16 hrs under a nitrogen atmosphere. Thesolvents were removed by evaporation. The residue was taken up in ethylacetate and washed successively with 1 N hydrochloric acid, 10% sodiumbicarbonate solution, and brine. The solution was dried with anhydroussodium sulfate and evaporated to give a dark residue. The residue wasdissolved in dichloromethane, 20 g of silica gel was added, and themixture was evaporated to dryness. This mixture was placed on top of achromatographic column of 150 g of silica gel in hexane. The column waseluted successively with 10, 15, 20, 25; and 30% ethyl acetate in hexaneto give 0.65 g (59% yield) of1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole. Mass spec:(m+H)⁺=304.0; calculated, 304.0. The R_(f)=0.22 on silica gel thin layerchromatography by elution with 70:30 hexane-ethyl acetate. Thepreparation was scaled up for Part C.

Part C: A mixture of 18.51 g (0.0609 mole) of1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole, 300 mL ofethanol, 0.6 mL of conc. hydrochloric acid, and 10 mL (9.75 g, 0.0974mole) of 2,4-pentanedione was refluxed with stirring under a nitrogenatmosphere for 4 hrs. The mixture was allowed to cool and the solventwas removed under reduced pressure. The residue was dissolved in ethylacetate. The solution was washed with 10% sodium bicarbonate solution,then with brine. The solution was dried with anhydrous sodium sulfateand evaporated to give 21.76 g of dark, tarry residue. The residue waschromatographed on silica gel by eluting in step gradients of 0, 10, 15,20, 25; and 30% ethyl acetate in hexane. The initial fraction is 17.6 g(78%) 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole;m.p. 105.8°. Mass spec: (m+H)⁺=368.0749; calculated, 368.0762 (⁷⁹Br).R_(f) =0.45 on silica gel thin layer chromatography with 70:30hexane-ethyl acetate.

EXAMPLE 65 1-(2-Bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole

A mixture of 4.00 g of1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole and 40 mLof 65% sulfuric acid was refluxed for one hour. The solution was cooledand poured onto ice. Conc. ammonium hydroxide was added until themixture was alkaline to pH paper. The mixture was extracted with ethylacetate. The solution was dissolved in 60:40 hexane-ethyl acetate andpassed through a short column of silica gel. The eluate was evaporated,and the residue was crystallized from 20 mL of hexane to give 2.45 g(66% yield) of 1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole.Mass spec: (m+H)⁺=343.0818; calculated, 343.0810. R_(f)=0.57 on silicagel with 70:30 hexane-ethyl acetate.

EXAMPLE 661-(2-Bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole

A mixture of 737 mg (2.00 mmole) of the product from Example 64 (PartB), 324 mg (2.00 mmole) of benzoylacetone and 25 mL of xylene was heatedin a flask equipped with a water separator for 2 hours. The solvent wasremoved by evaporation, and the residue chromatographed on silica gel,eluting in step gradients with 0, 5, 10; and 15% ethyl acetate inhexane. Both1-(2-bromo-4-isopropylphenyl)-3-cyano-4-methyl-6-phenyl-7-azaindole and1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-methyl-7-azaindole wereobtained. The R_(f) values were respectively 0.38 and 0.28 (silica gelwith 80:20 hexane-ethyl acetate). The assignment of the structures wasbased on the nmr data of the de-cyanylated compounds in Example 67.

EXAMPLE 67 1-(2-Bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole

A mixture 130 mg (0.302 mmole) of1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-4-phenyl-7-azaindole(Example 66) and 10 mL of 65% sulfuric acid were refluxed for one hour.The mixture was poured onto ice, Conc. ammonium hydroxide was addeduntil the mixture was basic to pH paper. The mixture was extracted withethyl acetate. The extract was evaporated and chromatographed on silicagel with 70:30 hexane-ethyl acetate. There was obtained 112 mg (92%yield) of 1-(2-bromo-4-isopropylphenyl)-6-methyl-4-phenyl-7-azaindole.Mass spec: (m+H)⁺=405.10; calculated, 405.10.

In the same way,1-(2-bromo-4-isopropylphenyl)-4-methyl-6-phenyl-7-azaindole wasobtained, mp 95.8°.

EXAMPLE 681-(2-Bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole

Part A: N-(2-bromo-4,6-dimethoxyphenyl)-aminomethylene-succinonitrilewas prepared from 2-bromo-4,6-dimethoxyaniline by the method describedin Example 64, Part A. Mass spec: (m+H)⁺=322.0; calculated, 322.16.R_(f)=0.19 (silica gel with 60:40 hexane-ethyl acetate).

Part B: The product from Part A was cyclized by the method described inExample 64, Part B to give1-(2-bromo-4,6-dimethoxy-phenyl)-2-amino-4-cyano-pyrrole (79% yield).R_(f)=0.19 (silica gel with 60:40 hexane-ethyl acetate).

Part C: The product from Part B was treated with 2,4-pentanedione asdescribed in Example 64, Part C to give1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole (92%yield). Mass spec: (m+H)⁺=388.0; calculated, 388.0. R_(f)=0.44 (silicagel with 60:40 hexane-ethyl acetate).

EXAMPLE 69 1-(2-bromo-4,6-dimethoxyphenyl,)-4,6-dimethyl-7-azaindole

A mixture of 200 mg of1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole and 10ml of 65% sulfuric acid was refluxed for one hour. The mixture wasworked up as described in Example 65 to give 185 mg of crude product. A40 mg portion was purified by preparative liquid chromatography on anitrile column using 95:5 1-chlorobutane-acetonitrile to give 11 mg of1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole. Mass spec:(m+H)⁺=360.9; calculated, 361.1.

EXAMPLE 701-(2-Bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole

Part A: A solution of 3.04 g of the product of Example 64 (Part B), 1.9mL (1.94 g; 14.9 mmole) of ethyl acetoacetate, and 0.1 mL of conc.hydrochloric acid in 30 mL of ethanol was refluxed for 16 hours. Aprecipitate formed upon cooling. The precipitate was removed byfiltration to give 1.68 g of crystals; mp 202.4° C., of1-(2-bromo-4-isopropylphenyl)-4-methyl-7-azaindole-6-one. TLC on silicagel with 70:30 hexane-ethyl acetate showed a single spot, R_(f)=0.29.Mass spec. (m+H)⁺=370.5; calcd., 370.05 (⁷⁹Br).

Part B: A mixture of 185 mg of the 7-azaindole-6-one (Part A) and 50 mlof phosphorus oxychloride was heated in an autoclave at 180° C. for 10hrs. The excess phosphorus oxychloride was removed by distillation atreduced pressure. The residue was distributed between ethyl acetate andwater. The ethyl acetate layer was separated and washed with 10% sodiumbicarbonate solution, then with brine. The solution was dried (Na₂SO₄)and evaporated. TLC of the residue on silica gel with 70:30 hexane-ethylacetate showed a major new product, R_(f)=0.52 with minor spots atR_(f)0.45 and 0.29. Chromatography on silica gel with step gradients of5, 10, 15, and 20% ethyl acetate in hexane gave 109 mg of the R_(f) 0.52product; mp 123.8° C. This is1-(2-bromo-4-isopropylphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole.

EXAMPLE 71 1-(2-Bromo-4-isopropylphenyl)-6-chloro-4-methyl-7-aziandole

A mixture of 52 mg of1-(2-bromo-4-isopropyphenyl)-6-chloro-3-cyano-4-methyl-7-azaindole and10 mL of 65% sulfuric acid was refluxed for one hour. The cooledsolution was poured onto ice, and 17 mL of conc. ammonium hydroxide wasadded. The alkaline mixture was extracted with ethyl acetate. Theextract was washed (brine), dried (Na₂SO₄), and evaporated. TLC of theresidue on silica gel with 70:30 hexane-ethyl acetate showed a major newspot, R_(f)=0.58; with a trace of unchanged starting material (R_(f)0.52). The crude product was purified by preparative TLC to give 39 mgof non-crystaline product, which slowly crystallized on standing. Massspec. (m+H)⁺=363.0247; calcd., 363.0264 (⁷⁹Br, ³⁵Cl).

EXAMPLE 72 1-(2-Bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole

To a solution of 1.085 g (5.07 mmole) of the product from Example 64(part B) and 0.80 mL (0.797 g; 6.03 mmole) of acetoacetaldehyde dimethylacetal in 20 mL of ethanol was added 0.10 mL of conc. hydrochloric acid.The mixture was refluxed for 16 hours, then cooled and evaporated togive a dark, thick oil. TLC on silica gel with 70:30 hexane-ethylacetate showed two major spots at R_(f) 0.47 and 0.41. The oil wasdissolved in ethyl acetate, 20 mL silica gel powder was added, and themixture was evaporated to dryness. The powdery residue was loaded on topof a column of 60 mL of silica gel in hexane. The column was eluted instep gradients of 0, 5, 10, 15, 20, and 25% ethyl acetate in hexane. Thefirst fraction to elute was 0.32 g of the desired1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole, Rf 0.47.The material can be crystallized from hexane to give 176 mg of crystals;mp 176.0° C. Mass spec. (m+H)⁺=354.0595; calcd., 354.0606.

EXAMPLE 73 1-(2-Bromo-4-isopropylphenyl)-6-methyl-7-azaindole

Material from Example 72 was treated with 65% sulfuric acid as describedin Example 65 to give the desired product as a viscous oil. TLC onsilica gel with 70:30 hexane-ethyl acetate showed Rf =0.57. Mass spec.(m+H)⁺=329.0641; calcd., 329.0653 (⁷⁹Br).

EXAMPLE 741-(2-Bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole

Part A: A solution of 1.24 g of1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole (Example 72)and 1.42 g of 85% 3-chloro-peroxybenzoic acid in 20 mL of chloroform wasrefluxed for 6 hrs. The mixture was cooled and washed first with 10%sodium bicarbonate solution, then with brine. The solution was dried(Na₂SO₄) and evaporated to give a residue. TLC on silica gel with 95:5dichloromethane-methanol showed a trace spot at R_(f) 0.88 and a majorspot at R_(f) 0.34. The material was purified by chromatography onsilica gel with dichoromethane, followed by 1% methanol indichloromethane, to give a trace of unchanged1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole (R_(f) 0.88)and 0.92 g of 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole7-oxide (R_(f)0.34); mp 179.2°. Mass spec. (m+H)⁺=370.0559; calcd.,370.0555 (⁷⁹Br).

Part B: A mixture of 370 mg of the 7-oxide (Part A) and 5 mL ofphosphorus oxychloride was refluxed for two hours. The solution wascooled, poured on ice, and stirred until most of the phosphorusoxychloride was hydrolysed. The mixture was made alkaline with conc.ammonium hydroxide and extracted with ethyl acetate. The extract wasdried (Na₂SO₄) and evaporated to give a viscous residue. TLC on silicagel with 95:5 dichloromethane-methanol showed a major spot atR_(f)=0.79. The material was purified by preparative TLC on silica gelwith 70:30 hexane-ethyl acetate to give crystals. Recrystallization fromhexane gave 158 mg of1-(2-bromo-4-isopropylphenyl)-4-chloro-3-cyano-6-methyl-7-azaindole; mp123.3° C. Mass spec. (m+H)⁺=388.0197; calcd., 388.0216 (⁷⁹Br, ³⁵Cl).

EXAMPLE 75 1-(2-Bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole

A mixture of 190 mg of the 3-cyano-7-azaindole (Example 71) and 5 mL of65% sulfuric acid was refluxed for 30 minutes. The solution was pouredonto ice and extracted with ethyl acetate. The extract was washed withbrine, dried (Na₂SO₄), and evaporated to give a residue. TLC of theresidue on silica gel with 60:40 hexane-ethyl acetate showed a majorspot at R_(f)=0.67. The residue was purified by preparative TLC to give130 mg of a viscous oil, which is1-(2-Bromo-4-isopropylphenyl)-4-chloro-6-methyl-7-azaindole. Mass spec.(m+H)⁺=363.0246; calcd., 363.0264 (⁷⁹Br, ³⁵Cl).

EXAMPLE 76N-[2-bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine

Part A: To 3.18 grams (25.6 mmol) of commercially available5-amino-2-methoxypyridine in a solution of methylene chloride (50 ml)and methanol (20 ml) was added benzyltrimethylammonium tribromide (10 g,25.6 mmol) and the mixture was stirred at room temperature for 24 hours.The solvent was then stripped and the resulting residue was taken up inwater and extracted (3×100 mL) with ethyl acetate. The organic extractswere dried with magnesium sulfate, filtered, and concentrated in vacuo.The crude material was chromatographed on silica using 30% ethyl acetatein hexanes as solvent to afford 5-amino-2-bromo-6-methoxypyridine.C₆H₇N₂OBr MS 203 (M+H)⁺.

Part B: The product of part A above was coupled to2-chloro-4,6-dimethylpyrimidine (Example 1; part A) using NaH (1.2 eq)in DMF to giveN-[2-bromo-6-methoxy-pyridin-3-yl]-4,6-dimethyl-2-pyrimidinamine.C₁₂H₁₃N₄OBr MS 309 (M+H)⁺.

Part C: The product of part B above was alkylated in the same manner asused in Example 4; part C to provide the title compound. C₁₄H₁₇N₄OBr MS337 (M+H)⁺.

EXAMPLE 77N-[3-bromo-5-methyl-pyridin-2-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine

Part A: A 1.0 gram (5.35 mmol) portion of commercially available2-amino-3-bromo-5-methylpyridine was coupled to2-chloro-4,6-dimethylpyrimidine (Example 1; part A) using NaH (1.2 eq)in DMF to giveN-[3-bromo-5-methyl-pyridin-2-yl]-4,6-dimethyl-2-pyrimidinamine.C₁₂H₁₃N₄Br MS 293 (M+H)⁺.

Part B: The product of part A was alkylated in the same manner as usedin Example 4; part C to provide the title compound. C₁₄H₁₇N₄Br MS 321(M+H)⁺.

EXAMPLE 78N-[6-methoxy-pyridin-3-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinamine

To 200 mg ofN-[2-bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4-6-dimethyl-2-pyrimidinaminein 25 ml dry DMF was added 500 mg K₂CO₃, 100 mg of CuI, and 0.4 mL ofmorpholine and the reaction was heated to reflux for 6 hour. Thereaction mixture was then filtered and poured into water and thenextracted with ethyl acetate (3×50 mL). The extracts were dried and thesolvent removed and the resulting residue was chromatographed on silicagel with 20% ethyl acetate in hexane as the solvent (rf 0.4) to providethe title compound. C₁₄H₁₈N₄O MS 259 (M+H)⁺.

EXAMPLE 79N-[2-bromo-6-methoxy-pyridin-3-yl]-N-ethyl-4-methyl-6-(4-morpholinyl)-1,3,5triazin-2-amine

Part A: To 2,4-dichloro-6-methyl-s-triazine (Part A, Example 23, 2.0grams, 12.3 mmol) in 50 mL of CH₂Cl₂ chilled to 0 degrees was addedmorpholine (1.1 mL, 12.3 mmol) and the reaction was allowed to come toroom temperature and stirred for 2 hours. The reaction was then pouredinto water and the layers separated. The aqueous layer was washed withCH₂Cl₂, (3×50 mL) and the organic layers were combined and dried. Thesolvent was stripped and the crude material was chromatographed onsilica with 30% ethyl acetate in hexane as the solvent to give2-chloro-4-(N-morpholino)-6-methyl-s-triazine. C₈H₁₁N₄OCl (M+H)⁺.

Part B: The product of Example 76; Part A (0.6 gram, 3.0 mmol) and theproduct of Example 79; Part A (0.63 gram, 3.0 mmol) in dioxane werestirred at room temperature for 24 hours. The reaction mixture pouredinto water then extracted with ethyl acetate (3×50 mL). The extractswere dried with magnesium sulfate, filtered, and concentrated in vacuo.The crude material was chromatographed on silica using 30% ethyl acetatein hexanes as solvent to afford the coupled material C₁₄H₁₇N₆O₂Br MS 381(M+H)⁺.

Part C: The product of part B above was alkylated in the same manner asused in Example 5; part C to provide the title compound. C₁₆H₂₁N₆O₂Br MS409 (M+H)⁺.

EXAMPLE 80N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N-methylamino)carbonyl-6-methylpyrimidinamine

Sodium hydride (60% in oil, 0.1 g, 2.4 mmol), washed with hexanes anddecanted twice, was suspended in anhydrous N,N-dimethylformamide (DMF)(5 mL) and a solution ofN-(2-bromo-⁴-(1-methylethyl)phenyl)-N-ethyl-4-((2-furylmethyl)-amino)carbonyl-6-methylpyrimidinamine(1.0 g, 2.2. mmol) in anhydrous DMF (5 mL) was added dropwise withstirring. After 30 min, iodomethane (0.37 g, 2.6 mmol) was added and thereaction mixture was stirred for 18 h. Water (50 mL) was added carefullyand the aqueous mix was extracted three times with chloroform. Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo to give a brown oil. Column chromatography (ethylacetate:hexanes::1:2) afforded the title product as a brown oil (850 mg,82% yield, R_(f) 0.35): NMR (CDCl₃ 300 MHz): 7.5 (d, 1H, J=9), 7.3 (d,1H, J=12), 7.25-7.2 (m, 1H), 7.12 (dd, 1H, J=8, 1), 6.8 (s, 1H), 6.3 (d,1H, J=12), 6.0 (br s, 0.5H), 5.9 (br s, 0.5H), 4.65 (br s, 2H), 4.2 (brs, 1H), 3.75-3.6 (m, 1H), 3.0-2.8 (m, 4H), 2.4 (br s, 3H), 1.40 (d, 6H,J=7), 1.2 (t, 3H, J=8);

CI-HRMS: Calcd (C₂₃H₂₇BrN₄O₂): 471.1396 (M+H); Found: 471.1387.

EXAMPLE 81N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino)carbonyl)-6-methylpyrimidinamine

Sodium hydride (60% in oil, 0.12 g, 3 mmol), washed with hexanes anddecanted twice, was suspended in anhydrous THF (5 mL) and a solution of4-piperidone ethylene glycol ketal (0.43 g, 3 mmol) in anhydrous THF (5mL) was added dropwise with stirring. The reaction mixture was heated toreflux temperature, stirred for 30 min and then cooled to ambienttemperature. A solution of methyl2-((2-bromo-4-(1-methylethyl)-phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylate(Example 18) (1.0 g, 2.54 mmol) in anhydrous THF (10 mL) was added andthe reaction mixture was stirred at room temperature for 98 h. Thereaction mixture was poured onto a 1N NaOH solution (100 mL), mixed andextracted three times with ethyl acetate and the combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give abrown oil. Column chromatography (chloroform:methanol::9:1) affordedN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)carbonyl-6-methylpyrimidinamineas an orange-yellow oil (260 mg, 52% yield, R_(f) 0.75):CI-HRMS: Calcd(C₂₄H₃₁BrN₄O₃): 503.16578 (M+H); Found: 503.16571.

EXAMPLE 82N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)carbonyl-6-methylpyrimidinamine

A solution-ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino)carbonyl)-6-methylpyrimidinamine(260 mg) in a mixture of a 1N HCl solution (2.5 mL) and THF (2.5 mL) wasstirred at reflux temperature for 20 h. The reaction mixture was pouredinto a 1N NaOH solution, and extracted three times with ethyl acetate.The combined organic layers were dried over MgSO₄, filtered andconcentrated in vacuo to give the title product as a yellow oil (240 mg,100% yield, R_(f) 0.75): NMR (CDCl₃, 300 MHz): 7.5 (s, 1H), 7.2 (d, 1H,J=8), 7.1 (d, 1H, J=8), 6.8 (br s, 1H), 4.3-4.1 (m, 1H), 3.95-3.85 (m,1H), 3.75-3.6 (m, 1H), 3.55-3.4 (m, 1H), 2.95-2.85 (m, 1H), 2.6-2.3 (m,4H), 2.0-1.6 (m, 2H), 1.4-1.15 (m, 12H); CI-HRMS: Calcd (C₂₂H₂₇BrN₄O₂):459.1396 (M+H); Found: 459.1386.

EXAMPLE 83N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)methyl-6-methylpyriimidinamine,hydrochloride salt

A solution of borane in tetrahydrofuran (1M, 29 mL, 29 mmol) was addeddropwise to a solution ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)carbonyl-6-methylpyrimidinamine(1.67 g, 3.3 mmol) in anhydrous THF (7 mL) with stirring under anitrogen atmosphere. The reaction mixture was heated to refluxtemperature and stirred for 20 h, then cooled to ambient temperature. Asolution of glacial acetic acid was added dropwise; then the reactionmixture was heated to reflux temperature and stirred for 4 h, thencooled to ambient temperature. The reaction mixture was concentrated invacuo; the residue was treated with excess 1N NaOH solution, andextracted three times with ethyl acetate. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give anoil. Column chromatography (ethyl acetate) afforded N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4,4-ethylenedioxy-piperidino)methyl-6-methylpyrimidinamineas a pale brown oil (860 mg): CI-MS, 489, 491 (M+H).

The ketal was dissolved in a mixture of a 33% HCl solution (10 mL) andTHF (5 mL). The resulting solution was stirred at reflux for 65 h, thencooled to ambient temperature and basified with a 1N NaOH solution. Theaqueous mix was extracted three times with ethyl acetate. The combinedorganic layers were dried over MgSO₄, filtered and concentrated in vacuoto give an oil. Column chromatography (ethyl acetate:hexanes::4:1)afforded the title product as its free base and as an oil (600 mg, 41%overall yield): CI-HRMS: Calcd (C₂₂H₂₉BrN₄O): 444.1603(M+H); Found:444.1594.

The above oil (0.55 g, 1.24 mmol) was dissolved in ether (5 mL) andtreated with a 1N HCl solution in ether. The resulting precipitate wascollected and washed with copious amounts of ether. Drying in vacuoafforded a white powder (500 mg, 84% yield): mp 186-188° C.;Anal.(C₂₂H₂₉BrN₄O-HCl): C, 54.92; H, 6.24; N, 11.65; Br, 16.64; Cl,7.39; Found: C, 54.62; H, 6.37; N, 11.41; Br, 16.57; Cl, 7.35.

EXAMPLE 84N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidinamine

To a mixture ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimidinamine(1.57 g, 4.3 mmol), triethylamine(2.5 mL, 17 mmol) and dichloromethane(15 mL) at 0° C. under a nitrogen atmosphere was added methanesulfonylchloride (0.54 g, 4.7 mmol) dropwise and the reaction mixture wasstirred at 0° C. for 1.5 h. It was then washed successively with anice-cold 1N HCl solution, a saturated NaHCO₃ solution and a saturatedNaCl solution. Drying the methylene chloride solution over MgSO₄,filtration and removal of solvent in vacuo gaveN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methanesulfonyloxymethyl-6-methylpyrimidinamineas a clear colorless oil (1.6 g): NMR (CDCl₃, 300 MHz): 7.5 (d, 1H,J=1), 7.25-7.1 (m, 2H), 6.5 (s, 1H), 5.05-4.9 (br s, 2H), 4.3-4.1 (m,1H), 3.8-3.6 (m, 1H), 3.0-2.85 (m, 1H), 2.8-2.6 (br s, 3H), 2.5-2.25 (brm, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS, 442, 444 (M+H).

To sodium hydride (60% in oil, 0.1 g, 2.4 mmol), washed with hexanes anddecanted twice, suspended in anhydrous THF (10 mL) was added imidazole(146 mg, 2.14 mmol) in one portion and the reaction mixture was warmedto reflux temperature and stirred for 2 h. A solution of the crudemesylate in anhydrous THF (10 mL) was added dropwise to the reactionmixture, which had been cooled to ambient temperature. The reactionmixture was stirred for 68 h, then it was poured onto water andextracted three times with ethyl acetate. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give anoil. Column chromatography (ethyl acetate) afforded (1)N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimidinamine(130 mg, 8% overall yield, R_(f) 0.7) and (2) the title product (600 mg,59% overall yield, R_(f) 0.07): NMR (CDCl₃, 300 MHz): 7.6-7.4 (m, 2H),7.2 (dd, 1H, J=7, 1), 7.15 (d, 1H, J=8), 7.05 (s, 1H), 7.0-6.8 (m, 1H),6.05 (s, 1H), 4.95-4.8 (m , 2H), 4.25-4.1 (m, 1H), 3.8-3.6 (m, 1H),3.0-2.85 (m, 1H), 2.4-2.1 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H,J=8); CI-HRMS: Calcd (C₂₀H₂₄BrN5): 413.1293 (M+H), Found: 413.1275.

EXAMPLE 85N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-(methoxyphenyl)methoxymethyl)-6-methylpyrimidinamine

To a mixture ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxymethyl-6-methylpyrimidinamine(1.0 g, 2.7 mmol), triethylamine (1.4 mL, 10 mmol) and dichloromethane(20 mL) at 0° C. under a nitrogen atmosphere was added methanesulfonylchloride (0.34 g, 3.0 mmol) dropwise. The reaction was performed as forExample 84, except the reaction time was 15 min.

Sodium hydride (0.12 g, 3 mmol) and 3-methoxybenzyl alcohol (0.41 g, 3mmol) were reacted in anhydrous THF (10 mL) as for Example 84. Asolution of the crude mesylate in anhydrous THF (10 mL) was addeddropwise. The reaction mixture was stirred at reflux temperature for 18h, cooled to room temperature, poured into a 1N NaOH solution andextracted three times with ethyl acetate. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give anoil. Column chromatography (ethyl acetate:hexanes::1:1) afforded thetitle product as a viscous yellow liquid (800 mg, 60% overall yield,R_(f) 0.7): NMR (CDCl₃, 300 MHz): 7.5 (s, 1H), 7.3-7.1 (m, 4H), 6.95-6.9(m, 2H), 6.85 (br d, 1H, J=8), 6.75 (s, 1H), 5.6 (br s, 2H), 4.45-4.3(m, 2H), 4.25-4.05 (m, 1H), 3.8 (s, 3H), 3.8-3.6 (m, 1H), 2.9 (septet,1H, J=7), 2.3 (br s, 3H), 1.3 (d, 6H, J=7), 1.2 (t, 3H, J=7); CI-HRMS:Calcd (C₂₅H₃₀BrN₃O₂): 484.1599; Found: 484.1592.

EXAMPLE 86N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamine

To a solution of n-butyl lithium in hexanes (2.4 M, 1.34 mL, 3.24 mmol)in anhydrous THF (5 mL) at −78° C. under a nitrogen atmosphere was added2-bromothiazole (0.49 g, 0.27 mL, 3.0 mmol) dropwise. After the additionwas complete, the reaction mixture was stirred at −78° C. for 30 min. Asolution of methyl2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate(Example 18) (1.0 g, 2.5 mmol) in anhydrous THF (10 mL) was addeddropwise. The reaction mixture was then warmed to −60° C. and stirredfor 4 h. A saturated aqueous solution of NaHCO₃ was added and thereaction mixture was warmed to ambient temperature. Three extractionswith ethyl acetate, followed by two washings of the combined organiclayers with water, drying over MgSO₄, filtration and concentration invacuo gave a dark brown oil. Column chromatography (ethyl acetate:hexanes::1:1) afforded the title product, a brown solid (950 mg, 85%yield, R_(f) 0.43): mp 97-98.5° C.; NMR (CDCl₃, 300 MHz):8.0 (s, 1H),7.60 (s, 1H), 7.4-7.2 (m, 4H, J=6), 3.05-2.9 (m, 1H), 2.8-2.7 (m, 1H),2.6 (br s, 3H), 1.4-1.2 (m, 9H); CI-HRMS Calcd: 445.0698 (M+H), Found:445.0699; Anal.(C₂₀H₂₁BrN₄S): C, 54.05; H, 4.73; N, 12.61; Br, 18.02; S,7.21; Found: C, 53.86; H, 4.66; N, 12.53; Br, 18.20; S, 7.46.

EXAMPLE 87N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidinamine

To a solution of 1-(dimethylaminomethyl)imidazole (0.63 g, 5 mmol) inanhydrous diethyl ether (50 mL) at −78° C. under a nitrogen atmospherewas added a solution of n-butyl lithium in hexanes (2.4 M, 2.1 mL, 5mmol) dropwise and the pale yellow suspension was stirred at −78° C. for1 h. Methyl2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate(Example 18) (1.47 g, 5 mmol) was added in one portion and the reactionmixture was warmed to room temperature over 23 h. A 1N HCl solution wasadded until pH=1 (test paper) and the reaction mixture was stirred for 4h. A 3N NaOH solution was added until the solution became basic (pH=10;test paper). Three extractions with ethyl acetate, drying the combinedorganic layers over MgSO₄, filtration and concentration in vacuo gave abrown oily solid. Column chromatography (chloroform:methanol::9:1)afforded the title product, a yellow glass (900 mg, 42% yield, R_(f)0.43): mp 75-76° C.; NMR (CDCl₃, 300 MHz): 12.2-12.1 (m, 1H), 7.7 (d,1H, J=1), 7.45-7.35 (m, 2H), 7.3-7.2 (m, 2H), 6.55 (br s, 1H), 4.3(sextet, 1H, J=7), 3.8 (sextet, 1H, J=7), 3.05 (septet, 1H, J=7), 2.65(br s, 3H), 1.4 (d, 6H, J=7), 1.3 (t, 3H, J=7); CI-HRMS: Calcd: 428.1086(M+H), Found: 428.1089; Anal (C₂₀H₂₄BrN₅O) C, 56.08; H, 5.18; N, 16.35;Br, 18.66; Found: C, 56.20; H, 5.10; N, 15.88; Br, 18.73.

EXAMPLE 88N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5-indolylcarbonyl)-6-methylpyrimidinamine

To a suspension of potassium hydride (35% in oil, 0.16 g, 1.4 mmol),washed with hexanes and decanted twice, in anhydrous ether (5 mL),cooled to 0° C. under a nitrogen atmosphere was added a solution of5-bromoindole (0.27 g, 1.4 mmol) in anhydrous ether. After being stirredfor 30 min., the reaction mixture was cooled to −78° C. and transferredvia cannula to a pre-cooled (−78° C.) mixture of t-butyl lithium (1.7 Min pentane, 1.6 mL, 2.7 mmol) in dry ether (5 mL). The resulting whitesuspension was stirred at −78° C. for 30 min and a solution of methyl2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate(Example 18) (0.5 g, 1.25 mmol) in anhydrous ether (5 mL) was addeddropwise. After quenching the reaction mixture as in Example 87; it wasextracted three times with ethyl acetate, followed by two washings ofthe combined organic layers with a saturated NaHCO₃ solution, dryingover MgSO₄, filtration and concentration in vacuo to give a dark brownoil. Column chromatography (ethyl acetate: hexanes::1:4) afforded thetitle product, a light brown solid (140 mg, 24% yield, R_(f) 0.2): mp77-79° C.; NMR (DMSO-d₆, 400 MHz, 90° C.): 11.6-11.35 (br s, 1H), 8.30(s, 1H), 7.75 (dd, 1H, J=8, 1), 7.55 (d, 1H, J=1), 7.4-7.35 (m, 2H),7.35-7.25 (m, 2H), 6.9 (s, 1H), 6.60-6.55 (m, 1H), 4.1-3.7 (m, 2H),2.95-2.8 (m, 1H), 2.4 (br s, 3H), 1.25-1.1 (m, 9H); Anal (C₂₅H₂₅BrN₄O):C, 62.90; H, 5.28; N, 11.74; Br, 16.74; Found: C, 63.13; H, 5.60; N,11.37; Br, 16.80.

EXAMPLE 89N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-fluorophenyl)carbonyl-6-methylpyrimidinamine

To a suspension of N,O-dimethylhydroxylamine hydrochloride (1.46 g, 15mmol) in benzene (20 mL) at 5-10° C. under a nitrogen atmosphere wasadded a solution of trimethyl aluminum in toluene (2 M, 7.5 mL, 15 mmol)dropwise and the reaction mixture was then warmed to ambient temperatureover 1 h. The reaction mixture was transferred to an addition funnel andadded dropwise to a solution of methyl2-(N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate(Example 18) (2.25 g, 5.73 mmol) in benzene (40 mL). The reactionmixture was heated at reflux and stirred for 16 h. After being cooled toroom temperature, the mixture was poured into a 5% HCl solution (100mL), mixed and extracted three times with ethyl acetate. The combinedorganic layers were dried over MgSO₄, filtered and concentrated in vacuoto give a brown oil. Column chromatography (ethyl acetate: hexanes::1:1)affordedN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-methyl-N-methoxycarboxamido)-6-methylpyrimidinamine(1.0 g, 41% yield, R_(f) 0.4): CI-MS, 421, 423 (M+H).

The crude amide was dissolved in anhydrous THF (10 mL). A solution of4-fluorophenylmagnesium bromide in ether (2 M, 1.25 mL, 2.5 mmol) wasadded dropwise and the reaction mixture was stirred for 22 h. Thereaction was quenched by pouring onto a 1 N NaOH solution (50 mL). Theaqueous solution was extracted three times with ethyl acetate. Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo to give an orange yellow oil. Column chromatography (ethylacetate:hexanes::1:9) afforded the title product as a yellow solid (700mg, 65% yield, R_(f) 0.5): mp 70° C.; NMR (CDCl₃, 300 MHz): 8.3-8.05 (m,2H), 7.55 (d, 1H, J=1), 7.2-6.75 (m, 5H), 4.85-4.7 (m, 1H), 4.3-4.15 (m,1H), 2.95 (septet, 1H, J=7), 2.5 (br s, 3H), 1.4-1.15 (m, 9H); CI-HRMS:Calcd(C₂₃H₂₃BrFN₃O): 456.1087 (M+H), Found: 456.1084.

EXAMPLE 90N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyriimidinamine

A mixture of methyl2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate(Example 18) (10 g, 25 mmol), ethanol (100 mL) and a 1N NaOH solution(250 mL) was stirred at reflux temperature for 18 h. After being cooledto ambient temperature, the reaction mixture was concentrated twofold invacuo and acidified with a concentrated HCl solution. Three extractionswith chloroform, drying the combined organic layers over MgSO₄,filtration and removal of solvent in vacuo gave a pale brown solid (9.0g, 95% yield): mp 102-104° C.; NMR (CDCl₃, 300 MHz): 7.55 (d, 1H, J=1),7.25-7.20 (m, 2H), 7.15 (d, 1H, J=7), 4.30-4.10 (m, 1H), 3.88-3.7 (m,1H), 3.00-2.85 (m, 1H), 2.55 (br s, 3H), 2.30 (br s, 1H), 1.30 (d, 6H,J=7), 1.20 (t, 3H, J=7); CI-HRMS: Calcd(C₁₇H₂₀BrN₃O): 378.0817(M+H);Found: 378.0813.

EXAMPLE 91N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidinamine

Cerium trichloride (4.9 g, 19.6 mmol) was dried, with magnetic stirring,at 180° C. in vacuo for 4 h. After being cooled to room temperature andplaced under a nitrogen atmosphere, the solid was stirred for 16 h inanhydrous THF (50 mL).

A solution ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamine(3.7 g, 9.8 mmol) in anhydrous THF (25 mL) was cooled with stirring to−78° C. under a nitrogen atmosphere. A solution of methyl lithium inether (1.4 M, 7 mL, 9.8 mmol) was added dropwise and the reactionmixture was stirred at −78° C. for 1 h. The CeCl₃ suspension wastransferred via cannula into the reaction mixture and stirring at −78°C. was continued for 5 h. A solution of methyl lithium in ether (1.4 M,7 mL, 9.8 mmol) was added dropwise and the reaction mixture was thenwarmed gradually to room temperature over 16 h. After cooling thereaction mixture to −78° C., the reaction was quenched with a 1 N HClsolution and warmed to room temperature. The resulting mixture wasextracted three times with ethyl acetate. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give anorange yellow oil. Column chromatography (ethyl acetate:hexanes::1:4)afforded the title product as an oil (2.5 g, 68% yield, R_(f) 0.5): NMR(CDCl₃, 300 MHz): 7.55 (d, 1H, J=1), 7.25-7.15 (m, 2H), 6.95 (s, 1H),4.30-4.10 (m, 1H), 3.90-3.70 (m, 1H), 3.00-2.85 (m, 1H), 2.80-2.05 (m,6H), 1.35-1.20 (m, 9H); CI-HRMS: Calcd (C₁₈H₂₂BrN3O): 376.1024 (M+H),Found: 376.1042.

EXAMPLE 92N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-methylpyrimidinamine(XU472)

Sodium borohydride (0.11 g, 2.8 mmol) was added to a solution ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridylcarbonyl)-6-methylpyrimidinamine(0.6 g, 1.4 mmol) in ethanol (5 mL). After being stirred for 71 h, thereaction mixture was concentrated in vacuo, treated with a 1 N NaOHsolution and extracted three times with ethyl acetate. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to give a colorless oil. Column chromatography(chloroform:methanol::9:1) afforded the title product as an oil (600 mg,96% yield, R_(f) 0.4): NMR (CDCl₃, 300 MHz): 8.65-8.45 (m, 2H), 7.55 (brs, 2H), 7.3-7.1 (m, 2H), 6.25-6.15 (m, 1H), 5.7-5.5 (m, 0.5H), 5.45-5.3(m, 0.5H), 5.15-4.95 (m, 1H), 4.3-4.1 (m, 1H), 3.9-3.7 (m, 1H), 3.0-2.85(m, 1H), 2.45-2.2 (m, 3H), 2.3-2.2 (m, 1H), 1.35-1.2 (m, 9H); CI-HRMS:Calcd (C₂₂H₂₅BrN4O): 441.1290 (M+H), Found: 441.1274.

EXAMPLE 93N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-(methoxyphenyl)-3-pyridyl-hydroxymethyl)-6-methylpyrimidinamine

A solution of 4-bromoanisole (0.2 g, 1.1 mmol) in anhydrous THF (10 mL)was cooled with stirring to −78° C. under a nitrogen atmosphere. Asolution of t-butyl lithium in pentane (1.7 M, 1.4 mL, 2.4 mmol) wasadded dropwise and the reaction mixture was stirred for 0.5 h. Asolution ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridyl-carbonyl)-6-methylpyrimidinamine(0.45 g, 1 mmol) in anhydrous THF (10 mL) was added dropwise and thereaction mixture was warmed gradually to ambient temperature over 18 h.The reaction mixture was poured onto a saturated NH₄Cl solution andextracted three times with ethyl acetate. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give anoil. Column chromatography (ethyl acetate:hexanes::4:1) afforded thetitle product as a pale brown glass (170 mg, 31% yield, R_(f)0.2): mp68-70° C.; NMR (CDCl₃, 300 MHz): 8.6-8.4 (m, 2H), 7.7-7.5 (m, 1H), 7.5(s, 1H), 7.25-7.05 (m, 6H), 6.95-6.75 (m, 2H), 6.25-6.2 (m, 1H),5.85-5.7 (m, 1H), 4.25-4.05 (m, 1H), 3.8 (br s, 3H), 3.95-3.75 (m, 1H),3.00-2.8. (m, 1H), 2.45-2.1 (br s, 3H), 1.35-1.15 (m, 9H); CI-HRMS:Calcd(C₂₉H31BrN₄O₂): 547.1709 (M+H), Found: 547.1709.

EXAMPLE 94N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyrazolyl)-6-methylpyiimidinamine,Hydrochloride Salt

Sodium (0.08 g, 3.5 mmol) was added to methanol (20 mL) with stirring.After the sodium reacted, a solution ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methyl-pyrimidinamine(1.0 g, 2.67 mmol) in methanol (5 mL) was added and the reaction mixturewas stirred for 5 min. Gold's reagent((dimethylaminomethyleneaminomethylene))dimethyl-ammonium chloride (0.66g, 4 mmol) was added and stirring was continued for 19 h. The reactionmixture was concentrated in vacuo; the residue was dissolved inchloroform and the solution was washed with a saturated NaHCO₃ solution,dried over MgSO₄ and filtered solvent removal in vacuo gave a brownsolid, which upon trituration with hexanes affordedN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-dimethylaminopropenoyl)-6-methylpyrimidinamineas a yellow solid (700 mg): NMR (CDCl₃, 300 MHz): 7.9-7.65 (br s, 1H),7.5 (s, 1H), 7.25-7.2 (m, 2H), 7.15 (s, 1H), 6.1-5.8 (br s, 1H),4.3-4.15 (m, 1H), 3.9-3.75 (m, 1H), 3.2-3.0 (br s, 3H), 3.0-2.85 (m,1H), 2.8-2.6 (br s, 3H), 2.5-2.3 (br s, 3H), 1.35-1.2 (m, 9H): CI-MS,431, 433 (M+H).

A solution of the above vinylogous amide and anhydrous hydrazine (0.15g, 4.7 mmol) in toluene (15 mL) was stirred at reflux temperature undera nitrogen atmosphere for 16 h. The reaction mixture was poured ontowater and extracted three times with ethyl acetate. The combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo to givean oil. Column chromatography (ether) afforded the free base of thetitle product as a pale yellow glass (600 mg, 59% overall yield, R_(f)0.4): NMR (CDCl₃, 300 MHz): 7.6 (s, 1H), 7.55 (s, 1H), 7.3-7.2 (m, 2H),6.8 (s, 1H), 6.75-6.6 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.7 (m, 1H),3.00-2.85 (m, 1H), 2.5-2.2 (br s, 3H), 1.3 (d, 6H, J=8), 1.25 (t, 3H,J=8); CI-HRMS: Calcd (C₁₉H₂₂BrN₅): 399.1137 (M+H), Found: 399.1140.

The free base was dissolved in ether and treated with an excess amountof a 1 N HCl solution in ether. The resulting precipitate was collectedand washed with copious amounts of ether. Drying in vacuo at 60° C.afforded the title product as a powder (500 mg, 72% yield) mp 235-237°C.; NMR (DMSO-d₆, 300 MHz): 7.9-7.7 (m, 1H), 7.6 (s, 1H), 7.4-7.3 (m,2H), 7.2 (s, 1H), 7.05-6.85 (m, 1H), 4.3-4.1 (m, 1H), 3.85-3.65 (m, 1H),3.05-2.9 (m, 1H), 2.45-2.1 (br m, 3H), 1.25 (d, 6H, J=8), 1.2 (t, 3H,J=8); Anal. (C₁₉H₂₂BrN₅-HCl): C, 52.75; H, 5.31; N, 16.03; Br, 18.29;Cl, 8.12; Found: C, 52.53; H, 5.28; N, 15.93; Br, 18.44; Cl, 8.17.

EXAMPLE 95N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminoethyl)-6-methylpyrimidinamine

A mixture ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methyl-pyrimidinamine(0.5 g, 1.33 mmol), ammonium acetate (1.1 g, 14 mmol), sodiumcyanoborohydride (59 mg, 0.9 mmol) and methanol (5 mL) was stirred atambient temperature for 90 h. A concentrated HCl solution was addeduntil the solution became acidic (pH=2), then the reaction mixture wasconcentrated in vacuo. The residue was taken up in water, basified witha concentrated NaOH solution and extracted three times with ether. Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo to give an oil. Column chromatography (ethyl acetate:hexanes::1: then chloroform:methanol:NH₄OH::95:5:0.5) gave (1)N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminothyl)-6-methyl-pyrimidinamine(80 mg, 16% yield, R_(f) 0.34 (ethyl acetate:hexanes::1;1)) and (2) thetitle product as a brown oil (180 mg, 36% yield, R_(f) 0.34(chloroform:methanol:NH₄OH::95:5:0.5)): NMR (CDCl₃, 300 MHz): 7.5 (d,1H, J=1), 7.2-7.1 (m, 2H), 6.4 (s, 1H), 4.25-4.05 (m, 1H), 3.9-3.65 (m,2H), 3.0-2.85 (m, 1H), 2.4-2.2 (br m, 3H), 1.9-1.6 (br m, 3H), 1.3 (d,6H, J=8), 1.2 (t, 3H, J=8); CI-HRMS (C₁₈H₂₅BrN₄): 377.1341 (M+H), Found:377.1330.

EXAMPLE 96N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1-methylethyl)-6-methylpyrimidinamine

A mixture ofN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6-methylpyrimidinamine(1.1 g, 2.7 mmol), triethylamine (1.5 mL, 11 mmol) and dichloromethane(15 mL) was stirred at 0° C. under a nitrogen atmosphere.Methanesulfonylchloride (364 mg, 3.2 mmol) was added dropwise and thereaction mixture was then stirred for 1.5 h. The resulting turbidsolution was washed successively with an ice-cold 1 N HCl solution, asaturated NaHCO₃ solution and a saturated NaCl solution. Drying overMgSO₄, filtration and removal of solvent in vacuo gaveN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-methanesulfonyloxyethyl)-6-methylpyrimidinamineas a clear colorless oil (1.0 g): NMR (CDCl₃, 300 MHz): 7.5 (d, 1H,J=1), 7.25-7.1 (m, 2H), 6.55 (s, 1H), 4.3-4.05 (m, 1H), 3.85-3.6 (m,1H), 3.0-2.5 (m, 4H), 2.5-2.05 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H,J=8); CI-MS, 456, 458 (M+H).

The crude mesylate was mixed with sodium cyanide (0.54 g, 11 mmol) inN,N-dimethylformamide (DMF) (20 mL) and stirred at reflux temperaturefor 67 h. After being cooled to room temperature, the reaction mix waspoured onto water (200 mL), mixed and extracted with ethyl acetate threetimes. The combined organic layers were dried over MgSO₄, filtered andconcentrated in vacuo to give an oil. Column chromatography (ethylacetate:hexanes::1:9) affordedN-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-cyanoethyl)-6-methylpyrimidinamineas an oil (440 mg, R_(f) 0.24): NMR (CDCl₃, 300 MHz): 7.5 (d, 1H, J=1),7.25-7.1 (m, 2H), 6.65-6.55 (m, 1H), 4.3-4.05 (m, 1H), 3.9-3.5 (m, 2H),3.0-2.85 (m, 1H), 2.55-2.0 (br m, 3H), 1.8-1.4 (br m, 3H), 1.4-1.1 (m,9H); CI-MS: 387, 389 (M+H).

A mixture of the crude cyanide, sodium azide (600 mg, 9 mmol), ammoniumchloride (492 mg, 9 mmol) and DMF (20 mL) was stirred at 100-105° C. for112 h. After being cooled to room temperature, the reaction mixture waspoured onto water (200 mL), basified with a 1 N NaOH solution (pH>10)and extracted three times with chloroform. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to give anoil. Column chromatography (chloroform:methanol::9:1) afforded a brownsolid (R_(f) 0.22). Recrystallization from ether gave the title productas a white solid (35 mg, 3% overall yield): mp 127-129° C.; NMR (CDCl₃,400 MHz): 7.75 (s, 0.4H), 7.7(s, 0.6H), 7.45 (d, 0.6H, J=8), 7.4 (d,0.4H, J=8), 7.3-7.2 (m, 2H), 6.5 (s, 0.4H), 6.48 (s, 0.6H), 4.28-4.0 (m,1.4H), 4.28-4.18 (m, 0.6H), 3.94-3.82 (m, 0.6H), 3.8-3.7 (m, 0.4H),3.1-3.0 (m, 1H), 2.45 (s, 3H), 1.5 (d, 3H, J=8), 1.4-1.3 (m. 5H),1.3-1.2 (m, 4H); CI-HRMS: 430.1355 (M+H); 430.1347.

EXAMPLE 972-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine

A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47.0 g, 252mmol) and 2-bromo-4-(2-propyl)aniline (54.0 g, 252 mmol) in dioxane (400mL) was stirred at reflux temperature for 20 h under a nitrogenatmosphere. The reaction mixture was cooled to ambient temperature andconcentrated on a rotary evaporator. The residue was treated with asaturated sodium bicarbonate solution and extracted three times withethyl acetate. The combined organic layers were dried over magnesiumsulfate and filtered. Solvent was removed in vacuo to provide a red oil.Column chromatography (ethyl acetate:hexanes::1:1) gave the titleproduct as a crude oil. Recrystallization from ether-hexanes, collectionby filtration and drying in vacuo afforded the title compound as a solid(42.8 g, 17% yield): mp 75-76° C.; NMR (CDCl₃, 300 MHz): 8.4 (d, 1H,J=8); 7.65 (br s, 1H), 7.4 (d, 1H, J=1), 7.3 (s, 1H), 7.2 (dd, 1H,J=8,1), 4.0 (s, 3H), 2.85 (septet, 1H, J=7), 2.5 (br s, 3H), 1.25 (d,6H, J=7); Anal. (C₁₆H₁₈BrN₃O₂): C, 52.76, H, 4.98; N, 11.54; Br, 21.94;Found: C, 52.71; H, 4.99; N, 11.38; Br, 21.83.

EXAMPLE 982-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)4-carbomethoxy-6-methylpyrimidine

To sodium hydride (60% in oil, 4.8 g, 120 mmol), washed with hexanes (50mL) twice and decanted in anhydrous tetrahydrofuran (150 mL) at ambienttemperature under a nitrogen atmosphere was stirred2-(N-(2-bromo-4-(2-propyl)phenylamino)-4-carbomethoxy-6-methylpyrimidine(42.8 g, 118 mmol) portionwise over 30 min. After gas evolutionsubsided, iodoethane (31.2 g, 16 mL, 200 mmol) was added in one portionand the reaction mixture was heated to a gentle reflux and stirred for24 h. After being cooled to room temperature, the reaction mixture wasquenched carefully with water and extracted three times with ethylacetate. The combined organic layers were washed with water twice, driedover magnesium sulfate and filtered. Solvent was removed in vacuo toafford a brown oil. Column chromatography (ether:hexanes::1:1) providedtwo fractions: (1)2-(N-(2-bromo-4-(2-propyl)phenylamino)-4-carbomethoxy-6-methylpyrimidine(4.6 g, 11% yield, R_(f)=0.8) and (2) the title product (20 g, R_(f)=0.7) as a crude oil.

The title product was recrystallized from hexanes and dried in vacuo togive a solid (18.0 g, 39% yield): mp 81-82° C., NMR(CDCl₃, 300 MHz): 7.5(br s, 1H), 7.25 (d, 1H, J=7), 7.15 (d, 1H, J=7), 7.1 (s, 1H), 4.3-4.1(m, 1H), 4.05-3.75 (m, 4H), 2.95 (septet, 1H, J=7), 2.3 (br s, 3H), 1.3(d, 6H, J=7), 1.25 (t, 3H, J=7); CI-HRMS: calcd: 392.0974 (M+H), found:392.0960.

EXAMPLE 992-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-6-methylpyrimidine-4-carboxylicacid, morpholine amide

To sodium hydride (60% in oil, 0.24 g, 6.0 mmol), washed with hexanestwice and decanted, and suspended in anhydrous tetrahydrofuran (10 mL)was added morpholine (0.52 g, 6.0 mmol) and the reaction mixture waswarmed to reflux temperature and stirred for 1 h. The reaction mixturewas then cooled to ambient temperature and2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-pyrimidine(2.0 g, 5.1 mmol) was added and stirring was continued for 26 h. Thereaction mixture was then poured onto a 1 N NaOH solution, stirred andextracted three times with ethyl acetate. The combined organic layerswere dried over magnesium sulfate, filtered and concentrated in vacuo.Column chromatography (ether) afforded the title compound as a solid(900 mg, 39% yield): mp 145° C.; NMR (CDCl₃, 300 MHz): 7.5 (d, 1H, J=1),7.2 (dd, 1H, J=7,1), 7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H),3.9-3.3 (m, 11H), 3.1-3.0 (m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H,J=7), 1.15 (t, 3H, J=7); Anal. (C₂₁H₂₇BrN₄O₂) Calcd: C, 56.38; H, 6.08;N, 12.52; Br, 17.86; Found: C, 56.07; H, 6.05; N, 12.29; Br, 18.08.

EXAMPLE 1002-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-(morpholinomethyl)-6-methylpyrimidine

To a solution of2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-6-methylpyrimidine-4-carboxylicacid, morpholine amide (750 mg, 1.72 mmol) in anhydrous tetrahydrofuran(1.4 mL) at ambient temperature under a nitrogen atmosphere was added asolution of borane in tetrahydrofuran (1 M, 3.6 mL, 3.6 mmol) dropwiseand the reaction mixture was heated at reflux temperature for 20 h.After cooling to room, acetic acid (3.5 mL) was slowly added and themixture was heated at reflux for 30 min. After being cooled to ambienttemperature, the reaction mixture was poured into a 3 N NaOH solutionand extracted three times with ethyl acetate. The combined organiclayers were dried over magnesium sulfate, filtered and concentrated invacuo. Column chromatography (ethyl acetate) afforded the title compoundas an oil (300 mg, 39% yield, R_(f) 0.3): NMR (CDCl₃, 300 MHz) 7.5 (s,1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 (s, 1H), 4.3-4.1 (m, 1H),3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H), 2.9 (septet, 1H, J=7), 2.55-2.35 (brm, 3H), 2.35-2.25 (m, 2H), 1.3 (d, 6H, J=7), 1.2 (t, 3H, J=7); CI-HRMS:calcd: 433.1603 (M+H), found: 433.1586.

EXAMPLE 101 9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chlropurine

Part A: Fuming nitric acid (40 mL) was added in portions to4,6-dihydroxy-2-methylpyrimidine while cooling the reaction flask onice. After completion of addition, the reaction was stirred anadditional 60 min over ice followed by another 60 min at roomtemperature. The reaction mixture was then poured over ice (60 g) andthe ice allowed to melt. A light pink solid was isolated by filtrationand washed with cold water (50 mL). The solid was dried in a vacuum ovenovernight to yield 22.6 g of product.

Part B: The product of Part A was added portionwise to phosphorusoxychloride (125 mL) under a nitrogen atmosphere. N,N-diethylaniline (25mL) was added portionwise and the reaction mixture was refluxed for 150min. then cooled to room temperature. The reaction mixture was pouredover ice (750 g) and stirred for 1 hr. The aqueous layer was extractedwith diethyl ether (4×400 mL) and the extracts combined. The extractswere washed with brine (300 mL) and the organic layer dried over Na₂SO₄.The dried organic layer was filtered and stripped down to a tan solid(21.51 g).

Part C: The product of Part B (3.0 g) was added to acetic acid (5.5 mL)and methanol (25 mL). This solution was added to iron powder (3.0 g) andthe reaction was stirred for two hrs at 60-65° C. The reaction wascooled to room temperature and the product was filtered. The filtratewas stripped to a brown solid, which was extracted with ethyl acetate(3×100 mL). The combined organic extracts were washed with NaOH (1 N,2×100 mL), water (100 mL), and brine (100 mL). The organic layer wasdried over Na₂SO₄, filtered, and stripped to yield (2.13 g) an amberliquid that solidified upon cooling. MS (M+H)⁺178.

Part D: The product of Part C (2.0 g), 2-bromo-4-isopropylaniline (2.4g), and diisopropylethylamine (1.52 g) were mixed and the reaction masswas heated to 160° C. for 25 min. Purification of the reaction mass byflash chromatography (CH₂Cl₂:MeOH, 50:1; silica) followed by strippingof the product-containing fractions yielded (1.45 g) an off white solid.MS (M+H)⁺356.

Part E: The product of Part D (1.32 g), triethylorthoformate (10 mL),and acetic anhydride (10 mL) were mixed under nitrogen and refluxed for4.5 hrs. The reaction mixture was reduced to an oil and water (50 mL)was added. The aqueous mixture was basified (pH 8) with solid Na₂CO₃ andextracted with CHCl₃ (3×80 mL). The combined organic extracts were driedover Na₂SO₄, filtered and stripped to yield an amber oil (1.63 g).Purification by flash chromatography (CH₂Cl₂:MeOH, 50:1; silica) yieldeda light amber glass 9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chloropurine (0.94 g). Mp 49-52° C. MS (M+H)⁺367.

EXAMPLE 102 9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-morpholinopurine

9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chloropurine (1.3 g) andmorpholine (10 mL) were combined under nitrogen and refluxed for 6 hrs.The reaction mixture was concentrated by rotovap and the residue waspurified by flash chromatography (CH₂C₂:MeOH, 50:1; silica) to yield ayellow solid (0.54 g). MS (M+H)⁺416, 418.

EXAMPLE 103 9[2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-chloropurine

Part A: Fuming nitric acid (40 mL) was added in portions to4,6-dihydroxy-2-methylpyrimidine while cooling the reaction flask onice. After completion of addition, the reaction was stirred anadditional 60 min over ice followed by another 60 min at roomtemperature. The reaction mass was then poured over ice (60 g) and theice allowed to melt. A light pink solid was isolated by filtration andwashed with cold water (50 mL). The solid was dried in a vacuum ovenovernight to yield 22.6 g of product.

Part B: The product of Part A was added portionwise to phosphorusoxychloride (125 mL) under a nitrogen atmosphere and N,N-diethylaniline(25 mL) was added portionwise. The reaction mixture was refluxed for 150min, cooled to room temperature, poured over ice (750 g) and stirred for1 hr. The aqueous layer was extracted with diethyl ether (4×400 mL) andthe extracts combined. The extracts were washed with brine (300 mL),dried over Na₂SO₄, filtered, and stripped down to a tan solid (21.51 g).

Part C: The product of Part B (6.5 g) was added to acetic acid (11 mL)and methanol (50 mL). This solution was added to iron powder (6.0 g),stirred for two hrs at 60-65° C., cooled to room temperature, andfiltered. The filtrate was stripped to a brown solid, which wasextracted with ethyl acetate (3×100 mL). The combined organic extractswere washed with NaOH (1 N, 2×100 mL), water (100 mL), and brine (100mL). The organic layer was dried over Na₂SO₄, filtered, and stripped toyield (4.75 g) an amber liquid that solidified upon cooling. MS(M+H)⁺178.

Part D: The product of Part C (4.75 g) and 2-bromo-4-isopropylaniline(5.71 g) were mixed and the reaction mass heated to 140° C. for 60 min.The reaction mass was suspended in CH₂Cl₂ (300 mL) and the organicsolution was washed with NaOH (1 N, 3×250 mL) and brine (250 mL). Theorganic phase was dried over Na₂SO₄, and stripped to a dark liquid (9.28g). The liquid was purified by flash chromatography (CH₂Cl₂:MeOH, 50:1;silica) to yield (6.27 g) a light red solid. MS (M+H)⁺356.

Part E: The product of Part D (2.0 g) was added to acetic acid (50%, 20mL) and sodium nitrite (0.407 g) in water (2.0 mL) was added dropwise atroom temperature. After 4.25 hrs, the reaction mixture was filtered andthe collected solid was purified by flash chromatography (CH₂Cl₂:MeOH,50:1; silica) to yield an orange oil 9[2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-chloropurine (0.75 g). MS(M+H)⁺368.

EXAMPLE 1049[2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-morpholinopurine

9 [2-bromo-4(2-propyl)phenyl]-8-aza-2-methyl-6-chloropurine (1.34g) andmorpholine (10 mL) were combined under nitrogen and refluxed for 2.5hrs. CH₂Cl₂ (200 mL) was added to the reaction mixture and the resultingsolution washed with water (2×100 mL) and brine (100 mL). The organicphase was dried over Na₂SO₄, concentrated by rotovap and the residuepurified by flash chromatography (CH₂Cl₂, silica) to yield a yellowsolid (0.62 g). MP 145-148° C. MS (M+H)⁺417, 419.

EXAMPLE 1052-(N-(2,4-dimethyoxypyrimidin-5-yl)-N-ethylamino)-4,6dimethylpyrimidine

Part A: 5-Nitrouracil (25 g) was added to phosphorus oxychloride (130mL) and N,N-diethylamine (32 mL) and the reaction was heated to refluxfor 70 min. under nitrogen. After cooling to room temperature, thereaction mixture was poured over ice (600 g) and the mixture stirreduntil it reached room temperature (60 min). The aqueous layer wasextracted with diethyl ether (4×300 mL). The extracts were combined,washed with brine (200 mL), and dried over Na₂SO₄. The organic layer wasthen stripped to yield an orange red liquid (17.69 g).

Part B: The product of Part A (17.69 g) in 60 mL methanol was addeddropwise to a solution of sodium methoxide (30% wt, 38 mL) while coolingthe flask in an ice bath. After addition was complete, the reactionmixture was stirred overnight at room temperature and then refluxed for4 hrs. After cooling to room temperature, the reaction mixture waspoured over ice (500 g) and the white precipitate that formed (10.38 g)was collected by filtration.

Part C: The product of Part B (4.1 g) and Pd/C (10% wt, 0.15 g) wereadded to ethanol (70 mL), methanol (10 mL) and water (1 mL) in a Parrreactor. The reaction mass was treated with hydrogen until TLC analysisshowed no starting material. The reaction mass was filtered throughcelite and the filtrate stripped yielding a tan solid (3.32 g).

Part D: The product of Part C (1.086 g) and2-chloro-4,6-dimethyl-pyrimidine (1.0 g) were dissolved in THF (50 mL)under nitrogen. Sodium hydride (0.336 g, 60% wt dispersion in oil) wasadded portionwise. After addition, the reaction was refluxed for 5.5hrs, cooled to room temperature and the solid removed by filtration. Thefiltrate was concentrated and purified by flash chromatography(CH₂C₂:MeOH, 90:10, silica) to give a solid (0.52 g). MS (M+H)⁺262.

Part E: The product of Part D (2.0 g) and iodoethane (1.49 g) weredissolved in dimethylformamide (20 mL) under nitrogen. Sodium hydride(0.383 g, 60% wt dispersion in oil) was added portionwise. Afteraddition, stirring was continued at room temperature for 22 hrs. Water(200 mL) was added and the mixture was extracted with ethyl acetate(3×200 mL). The combined extracts were washed with water (100 mL) andbrine (100 mL), dried over Na₂SO₄, filtered, and stripped to give anamber liquid2-(N-(2,4-dimethyoxypyrimidin-5-yl)-N-ethylamino)-4,6-dimethylpyrimidine(2.68 g). MS (M+H)+290.

Many of the compounds described above may be converted to their salts byaddition of the corresponding acid in a solution of the compound in anorganic solvent. The choice of addition salt described above is notintended to limit the invention, and is intended to be illustrative ofthe generality of the described syntheses. Physical properties ofrepresentative compounds that can be synthesized utilizing the methodsdescribed above are provided in the tables below (Table 1 through Table17). The column in the tables headed “Synth. Ex.” refers to thesynthesis examples 1-105; supra. The designations “MS” and “HRMS” referto low and high resolution mass spectral data, respectively.

TABLE 1

Synth. Ex. Ex. R¹ R³ R⁴ X, X′ R⁵ mp, ° C.  1*  1 CH₃ CH₃ CH₃ Br, H CH₃120-121  2* CH₃ CH₃ CH₃ CH₃O, H CH₃O 112-113  3* CH₃ CH₃ allyl Br, H H127-129  4*  2 CH₃ CH₃ CH₃ Br, H iC₃H₇ 163-164  5 CH₃ CH₃ C₂H₅ Br, H H 94-95  6 CH₃ morpholino CH₃ Br, H CH₃  40-42  7 CH₃ CH₃ C₂H₅ CH₃O, HCH₃O 120-121  8 CH₃ CH₃ CH₃ Br, H Br 101-103  9*  3 CH₃ CH₃ CH₃ Br, HC₂H₅ 126-127  10* CH₃ CH₃ C₂H₅ Br, H tC₄H₉ 191-193  11* CH₃ CH₃ CH₃ Br,H tC₄H₉ 193-195  12 CH₃ CH₃ CH₃ Br, H CF₃ 106-107  13* CH₃ CH₃ C₂H₅ Br,H CF₃ 125-130  14 CH₃ CH₃ CH₃ CH₃O, CH₃O 145-146 CH₃O  15 CH₃ CH₃ C₂H₅CH₃O, CH₃O 115-116 CH₃O  16*  4 CH₃ morpholino C₂H₅ Br, H iC₃H₇ 219-222 17* CH₃ morpholino allyl Br, H iC₃H₇ 208-211  18* CH₃ CH₃ allyl Br, HnC₄H₉ 116-118  19* CH₃ CH₃ C₂H₅ Br, H nC₄H₉ 124-126  20 CH₃ CH₃ nC₃H₇Br, H nC₄H₉  49-50  21*  5 CH₃ CH₃ C₂H₅ Br, H iC₃H₇ 151-153  22* CH₃ CH₃C₂H₅ Br, H cC₆H₁₁ 170-172  23* C₂H₅ C₂H₅ C₂H₅ Br, H iC₃H₇ 120-121  24*C₂H₅ C₂H₅ C₂H₅ Br, H nC₄H₉ 116-118  25 CH₃ 4-CHO-piperazino C₂H₅ Br, HiC₃H₇  61-63  26* CH₃ CH₃ allyl Br, H iC₃H₇ 141-142  27* CH₃ CH₃ C₂H₅ I,H iC₃H₇ 149-150  28 CH₃ CF₃ C₂H₅ Br, H iC₃H₇ liquid  29*  6 CH₃ CH₃ C₂H₅Br, H C₂H₄—OCH₃ 117-119  30  7 CH₃ 4-morpholino C₂H₅ I, H iC₃H₇  96-98 31*  8 CH₃ 2-thiopheno C₂H₅ Br, H iC₃H₇  95-97  32 CH₃ CH₃ CH₂CN Br, HiC₃H₇  33*  9 CH₃ CH₃ CH₂cyclopropyl Br, H iC₃H₇ 146-148  34 10 CH₃ CH₃propargyl Br, H iC₃H₇ MS  35 11 CH₃ CH₃ C₂H₅ I, H C₂H₄—OCH₃  36 CH₃ CH₃C₂H₅ I, H CH₂—OCH₃  37* CH₃ 4-allyloxy-piperidin-1-yl C₂H₅ Br, H iC₃H₇ 38 CH₃ morpholino C₂H₅ I, H CH₂—OCH₃  39 CH₃ CH₃ C₂H₅ CH₃S, H CH₂—OCH₃ 40 CH₃ CH₃ C₂H₅ (CH₃)₂N, CH₂—OCH₃ H  41 CH₃ CH₃ C₂H₅ CH₃S, H iC₃H₇  42CH₃ CH₃ C₂H₅ (CH₃)₂N, iC₃H₇ H  43 CH₃ CH₃ C₂H₅ CH₃S, H CH₃S  44 CH₃ CH₃C₂H₅ CH₃S, H CH₂—SCH₃  45 CH₃ CH₃ C₂H₅ Br, Br iC₃H₇  46 CH₃thiomorpholino C₂H₅ Br, Br iC₃H₇  47 CH₃ CH₃ C₂H₅ I, H I  48 CH₃morpholino C₂H₅ I, H I  49* 12 H CH₃ C₂H₅ Br, H iC₃H₇ 145-147  50 13 CH₃N(CH₃)CH₂—CH₂OH C₂H₅ Br, H iC₃H₇ HRMS  51* CH₃ CH₃ CH₂CH₃ CH₃O, CH₃ CH₃O 52* CH₃ CH₃ CH₃ H, H I 175-177  53* CH₃ CH₃ CH₃ I, H H 164-166  54* CH₃CH₃ CH₃ CF₃, H H  55* CH₃ CH₃ CH₂CH₃ Br, H C₂H₄—OCH₂CH₃ 127-129  56 14CH₃ thiomorpholino-S-oxide C₂H₅ I, H iC₃H₇  52-55  57* 15 CH₃ CH₃ C₂H₅Br, H O—iC₃H₇ MS  58 16 CH₃ C(═O)-4-morpholino C₂H₅ Br, H iC₃H₇ 145  5917 CH₃ CH₂-4-morpholino C₂H₅ Br, H iC₃H₇ liquid  60 CH₃C(═O)-1-piperidinyl C₂H₅ Br, H iC₃H₇ 107-108  61 18 CH₃ C(═O)OCH₃ C₂H₅Br, H iC₃H₇  81-82  62 CH₃ C(═O)NH-cyclohexyl C₂H₅ Br, H iC₃H₇ 115  6319 CH₃ C(═O)-4-methyl)-1-piperazinyl C₂H₅ Br, H iC₃H₇  81-82  64 20 CH₃CH₃ C₂H₅ Br, H CH₂—CH₂OH  58-60  65* 21 CH₃ CH₃ CH₃ OCH₃, H CH₃  66* CH₃CH₃ CH₃ H, H iC₃H₇  67 CF₃ CH₃ C₂H₅ Br, H iC₃H₇  68* CH₃ CH₃ CH₃ H, H I175-177  69* CH₃ CH₃ CH₃ CF₃, H H  70* CH₃ CH₃ CH₂CN Br, H iC₃H₇  71*CH₃ CH₃ CH₃ Br, H H  72* CH₃ (2-methoxymethyl)-1-pyrrolyl CH₃ Br, H H 73 22 CH₃ 4-thiomorpholino C₂H₅ I, H iC₃H₇  51-53  73* 22 CH₃4-thiomorpholino C₂H₅ I, H iC₃H₇ 234-236  74 CH₃ 4-hydroxy-1-piperidinylC₂H₅ Br, H iC₃H₇  61-63 138 24 CH₃ CH₂OH CH₃ Br, H iC₃H₇ oil, MS 139 25CH₃ CH₂OCH₃ CH₃ Br, H iC₃H₇ oil, MS 140 26 CH₃ SCH₃ C₂H₅ Br, H iC₃H₇oil, MS 141 CH₃ CH₃ C₂H₅ CH₃O, Cl CH₃O  99-102 142 CH₃

C₂H₅ Br, H iC₃H₇  78-81 143* CH₃

C₂H₅ Br, H iC₃H₇ 131-135 144* CH₃

C_(2H) ₅ Br, H iC₃H₇  98-102 145 CH₃ CH₃ H CH₃O, Cl CH₃O 170-173 146*CH₃ NHNH₂ C₂H₅ Br, H iC₃H₇ 117-121 147 CH₃

C₂H₅ Br, H iC₃H₇ oil, MS 148 CH₃

C₂H₅ Br, H iC₃H₇ oil, MS 149 CH₃ OCH₂Ph C₂H₅ Br, H iC₃H₇ oil, MS 150 CH₃O(CH₂)₃SCH₃ C₂H₅ Br, H iC₃H₇ oil, MS 152 CH₃

C₂H₅ Br, H iC₃H₇ oil, MS 153 CH₃

C₂H₅ Br, H iC₃H₇ oil, MS 154 CH₃ Cl C₂H₅ Br, H iC₃H₇ oil, MS 155 CH₃ NH₂C₂H₅ Br, H iC₃H₇ oil, MS 156 CH₃ O(CH₂)₃SO₂CH₃ C₂H₅ Br, H iC₃H₇ oil, MS157 CH₃

C₂H₅ Br, H iC₃H₇ oil, MS 158 CH₃

C₂H₅ Br, H iC₃H₇ oil, MS 159 27 CH₃ SO₂CH₃ C₂H₅ Br, H iC₃H₇ oil, MS 16028 CH₃ SOCH₃ C₂H₅ Br, H iC₃H₇ oil, MS 161* CH₃ O(CH₂)₂N(CH₃)₂ C₂H₅ Br, HiC₃H₇ 143-146 162 CH₃ O(CH₂)₃SOCH₃ C₂H₅ Br, H iC₃H₇ oil, MS 163 CH₃NH(CH₂)₂N(CH₃)₂ C₂H₅ Br, H iC₃H₇ oil, MS 164 CH₃ NH(CH₂)₄NH₂ C₂H₅ Br, HiC₃H₇ oil, MS 165 31 CH₃ morpholino allyl I, H iC₃H₇ 109-112 166 34 CH₃thiomorpholino H Br, Br iC₃H₇ 194-195 167 32 CH₃ Cl C₂H₅ I, H iC₃H₇liquid 168 35 CH₃ CH₃ C₂H₅ SCH₃, H iC₃H₇  64-66 169 37 CH₃ CH₃ C₂H₅S(O)CH₃, iC₃H₇ 144-146 H 170* 36 CH₃ CH₃ C₂H₅ SCH₃, H iC₃H₇ 141-142 17138 CH₃ thiazolidino C₂H₅ I, H iC₃H₇ liquid 172 39 CH₃ CH₃ C₂H₅ I, HCH₃OCH₂ liquid 173* 40 CH₃ CH₃ C₃H₆ S—, H iC₃H₇ 157-159 174 41 CH₃ CH₃C₂H₅ S(O)₂CH₃, iC₃H₇ 174-176 H 175* 42 CH₃ CH₃ C₂H₅ SC₂H₅, H iC₃H₇128-130 176 43 CH₃ CH₃ C₂H₅ SC₂H₅, H CH₃CNO—CH₃  77-78 177 33 CH₃N-methyl prolinol C₂H₅ SCH₃, H iC₃H₇ 101-103 178 44 CH₃ CH₃ C₂H₅ SCH₃, HCH₃CNO—CH₃ 106-108 179 45 CH₃ CH₃ C₂H₅ S(O)₂CH₃, CH₃CNO—CH₃ 151-154 H180 46 CH₃ CH₃ C₂H₅ SCH₃, H Br  91-93 181 47 CH₃ CH₃ iC₃H₇ SCH₃, H C₂H₅ 85-87 182* 48 CH₃ CH₃ C₂H₅ SCH₃, H C₂H₅ 140-141 183 49 CH₃ CH₃ C₂H₅SCH₃, H CH₃NCO—CH₃ 158-160 184 50 CH₃ CH₃ C₂H₅ SCH₃, H CO₂C₂H₅  99-100185 51 CH₃ CH₃ C₂H₅ SCH₃, H OCH₃ 128-130 186 52 CH₃ CH₃ C₂H₅ SCH₃, H CN 99-100 187 53 CH₃ CH₃ C₂H₅ SCH₃, H COCH₃ 125-126 188 54 CH₃ CH₃ C₂H₅SCH₃, H COC₂H₅ 139-141 189 55 CH₃ CH₃ C₂H₅ SCH₃, H CH(OCH₃)CH₃ liquid190 56 CH₃ CH₃ C₂H₅ SCH₃, H NHCH₃ 141-142 191 57 CH₃ CH₃ C₂H₅ SCH₃, HN(CH₃)₂ 119-120 192 CH₃ pyrrolidino C₂H₅ Br, H iC₃H₇ 106-107 193 CH₃pyrrolidino CH₃ Br, H iC₃H₇ 119-120 194 C₂H₅ piperidino CH₃ Br, H iC₃H₇211-212 195 CH₃ piperidino CH₃ Br, H iC₃H₇ 186-187 196 CH₃ CH₃ C₃H₇ Br,H iC₃H₇ 150-151 197 CH₃ CH₃ C₄H₉ Br, H iC₃H₇ 159-160 198 CH₃ CH₃N,N-diethylacetamidino Br, H iC₃H₇ 101-102 199 CH₃ CH₃N,N-diethylaminoethyl Br, H iC₃H₇  65-66 200 CH₃ CH₃N,N-dimethylaminoethyl Br, H iC₃H₇ 118-120 201 CH₃ CH₃ Et Br, H OEt HRMS202 CH₃ CH₃ Et Br, OMe OMe 113-115 203 CH₃ CH₃ H Br, OMe OMe 177-179 204CH₃ CH₃ H Br, H OMe 118-119 205 CH₃ CH₃ Allyl Br, OMe OMe  88-90 206 CH₃CH₃ Et Br, H OMe HRMS 207 CH₃ CH₂OCH₃ Et I, H iC₃H₇ HRMS 208 CH₃CH₂O(4-methoxyphenyl) Et Br, H iC₃H₇ HRMS 209 CH₃ CH₂OPh Et Br, H iC₃H₇HRMS 210 CH₃ CH₂O(2-pyridyl) Et Br, H iC₃H₇ HRMS 211 CH₃CH₂OCH₂(4-methyl benzoate) Et Br, H iC₃H₇ HRMS 212 CH₃CH₂OCH₂(3,4,5-trimethoxyphenyl) Et Br, H iC₃H₇ HRMS 213 CH₃CH₂O(2-pyrimidinyl) Et Br, H iC₃H₇ HRMS 214 CH₃CH₂O(3,4,5-trimethoxyphenyl) Et Br, H iC₃H₇ HRMS 215 CH₃CH₂O(3-(N,N-dimethyl)anilino) Et Br, H iC₃H₇ HRMS 216 CH₃CH₂OCH₂(3-pyridyl) Et Br, H iC₃H₇ HRMS 217 CH₃ CH₂O(4-methyl benzoate)Et Br, H iC₃H₇ 136-139 218 CH₃ CH₂O(4-(1-imidazole)phenyl) Et Br, HiC₃H₇ HRMS 219 CH₃ CH₂OCH₂(4-pyridyl) Et Br, H iC₃H₇ HRMS 220 CH₃CH₂OCH₃ Et Br, H iC₃H₇ 221 CH₃ CH₂OCH₂(2-furyl) Et Br, H iC₃H₇ HRMS 22258 CH₃ CHO Et Br, H iC₃H₇ HRMS 223 CH₃ CH₃ H Br, Br OMe 175-177 224 63CH₃ CH₃ Et Br, Br OEt 107-108 225 59 CH₃ CH₂OCH₂CH₂OH Et Br, H iC₃H₇HRMS 226 CH₃ CH₃ Et Br, Br OMe 101-103 227 CH₃ CH₂OCH₂CH₂OCH₃ Et Br, HiC₃H₇ HRMS 228 CH₃ CH₃ H Br, Br OEt 165-167 229 CH₃CH₂OCH₂CO(4-morpholino) Et Br, H iC₃H₇ HRMS 230 60 CH₃ CH₃ Et Br, OH OMe157-160 231 CH₃ CH₂OCH₂CH₂(4-morpholino) Et Br, H iC₃H₇ HRMS 268 CH₃(4-(2-methoxyphenyl)piperazinyl)carbonyl Et Br, H iC₃H₇  57-60 269 CH₃(1,2,3,4-tetrahydroquinolinyl)carbonyl Et Br, H iC₃H₇ 143-145 270 CH₃(2-furylmethyl)aminocarbonyl Et Br, H iC₃H₇  87-88 271 CH₃ MeNHCO Et Br,H iC₃H₇ oil, MS 272 CH₃ (4-(pyrazinyl)piperazino)carbonyl Et Br, H iC₃H₇ 51-53 273 CH₃ (4-(2-pyrimidyl)piperazino)carbonyl Et Br, H iC₃H₇114-116 274 CH₃ (4-(2-pyridyl)piperazino)carbonyl Et Br, H iC₃H₇ oil, MS275 CH₃ (4-(2-methoxyphenyl)piperazinyl)methyl, HCl salt Et Br, H iC₃H₇102-104 276 CH₃ N-(2-furylmethyl)-N-methylaminomethyl Et Br, H iC₃H₇oil, MS 277 CH₃ (1,2,3,4-tetrahydroquinolinyl)methyl, HCl salt Et Br, HiC₃H₇  88-90 278 CH₃ (4-pyrazinylpiperazino)methyl Et Br, H iC₃H₇ oil,MS 279 CH₃ dimethylaminomethyl Et Br, H iC₃H₇ oil, MS 280 CH₃(4-(2-pyridyl)piperazino)methyl, HCl salt Et Br, H iC₃H₇ 117-119 281 CH₃(4-(2-pyrimidyl)piperazino)methyl, HCl salt Et Br, H iC₃H₇ 125-127 282CH₃ Me₂NCO Et Br, H iC₃H₇  80-82 283 CH₃ 3-indoylcarbonyl, HCL salt EtBr, H iC₃H₇ 105-107 284 CH₃ 3-pyridylcarbonyl Et Br, H iC₃H₇ 165-167 285CH₃ 3-phenylcarbonyl Et Br, H iC₃H₇ oil, MS 286 CH₃ 3-pyrazolylcarbonylEt Br, H iC₃H₇ 171-173 287 CH₃ 4-methoxyphenylcarbonyl Et Br, H iC₃H₇104-106 288 CH₃ 2-furylcarbonyl Et Br, H iC₃H₇ 136-138 289 CH₃bis(4-methoxyphenyl)hydroxymethyl Et Br, H iC₃H₇  63-65 290 CH₃bis(2-furyl)hydroxymethyl Et Br, H iC₃H₇  97-99 291 CH₃(2-furyl)hydroxymethyl Et Br, H iC₃H₇ oil, MS 292 CH₃(4-methoxyphenyl)hydroxymethyl Et Br, H iC₃H₇ oil, MS 293 CH₃diphenylhydroxymethyl Et Br, H iC₃H₇  56-58 294 CH₃bis(4-pyridyl)hydroxymethyl Et Br, H iC₃H₇  68-70 295 CH₃(1-hydroxy-1-methyl)ethyl Et Br, H iC₃H₇ oil, MS 296 CH₃ 1-hydroxyethylEt Br, H iC₃H₇ oil, MS *Hydrochloride salt

TABLE 2

Ex. R¹ R³ R⁴ X, X′ R⁵ mp, ° C.  75 CH₃ CH₃ CH₃ Br, H CH₃  76 CH₃ CH₃ CH₃CH₃O, H CH₃O  77 CH₃ CH₃ allyl Br, H H  78* CH₃ CH₃ CH₃ Br, H iC₃H₇178-179  79 CH₃ CH₃ C₂H₅ Br, H H  80 CH₃ morpholino CH₃ Br, H CH₃  81CH₃ CH₃ CH₂H₅ CH₃O, H CH₃O  82 CH₃ CH₃ CH₃ Br, H Br  83 CH₃ CH₃ CH₃ Br,H CH₂H₅  84 CH₃ CH₃ C₂H₅ Br, H tC₄H₉  85 CH₃ CH₃ CH₃ Br, H tC₄H₉  86 CH₃CH₃ CH₃ Br, H CF₃  87 CH₃ CH₃ CH₂H₅ Br, H CF₃  88 CH₃ CH₃ CH₃ CH₃O, CH₃OCH₃O  89 CH₃ CH₃ C₂H₅ CH₃O, CH₃O CH₃O  90 CH₃ morpholino C₂H₅ Br, HiC₃H₇  91 CH₃ morpholino allyl Br, H iC₃H₇  92 CH₃ CH₃ allyl Br, H nC₄H₉ 93 CH₃ CH₃ C₂H₅ Br, H nC₄H₉  94 CH₃ CH₃ nC₃H₇ Br, H nC₄H₉  95* CH₃ CH₃C₂H₅ Br, H iC₃H₇ 194-196  96 CH₃ CH₃ C₂H₅ Br, H cC₆H₁₁  97 C₂H₅ C₂H₅C₂H₅ Br, H iC₃H₇  98 C₂H₅ C₂H₅ C₂H₅ Br, H nC₄H₉  99 CH₃ 4-CHO-piperazinoC₂H₅ Br, H iC₃H₇ 100 CH₃ CH₃ allyl Br, H iC₃H₇ 101 CH₃ CH₃ C₂H₅ I, HiC₃H₇ 102 CH₃ CF₃ C₂H₅ Br, H iC₃H₇ 103 CH₃ CH₃ C₂H₅ Br, H C₂H₄—OCH₃ 104CH₃ morpholino C₂H₅ I, H iC₃H₇ 105 CH₃ 2-thiopheno C₂H₅ Br, H iC₃H₇ 106CH₃ CH₃ CH₂CN Br, H iC₃H₇ 107 CH₃ CH₃ CH₂cyclopropyl Br, H iC₃H₇ 108 CH₃CH₃ propargyl Br, H iC₃H₇ 109 CH₃ CH₃ C₂H₅ I, H C₂H₄—OCH₃ 110 CH₃ CH₃C₂H₅ I, H CH₂—OCH₃ 111 CH₃ morpholino C₂H₅ I, H C₂H₄—OCH₃ 112 CH₃morpholino C₂H₅ I, H CH₂—OCH₃ 113 CH₃ CH₃ C₂H₅ CH₃S, H CH₂—OCH₃ 114 CH₃CH₃ C₂H₅ (CH₃)₂N, H CH₂—OCH₃ 115 CH₃ CH₃ C₂H₅ CH₃S, H iC₃H₇ 116 CH₃ CH₃C₂H₅ (CH₃)₂N, H iC₃H₇ 117 CH₃ CH₃ C₂H₅ CH₃S, H CH₃S 118 CH₃ CH₃ C₂H₅CH₃S, H CH₂—SCH₃ 119 CH₃ CH₃ C₂H₅ Br, Br iC₃H₇ 120 CH₃ thiomorpholinoC₂H₅ Br, Br iC₃H₇ 121 CH₃ CH₃ C₂H₅ I, H I 122 CH₃ morpholino C₂H₅ I, H I123 H CH₃ C₂H₅ Br, H iC₃H₇ 124 CH₃ N(CH₃)CH₂—CH₂OH C₂H₅ Br, H iC₃H₇ 125CH₃ CH₃ CH₂CH₃ CH₃O, CH₃O CH₃ 126 CH₃ CH₃ CH₃ H, H I 127 CH₃ CH₃ CH₃ I,H H 128 CH₃ CH₃ CH₃ CF₃, H H 129* H H CH₂CH₃ Br, H iC₃H₇ *Hydrochloridesalt

TABLE 3

Ex. R¹ R³ R⁴ X, X′ R⁵ mp, ° C. 130* CH₃O CH₃O CH₂CH₃ Br, H iC₃H₇ 104-106*Hydrochloride salt

TABLE 4

Ex. R¹ R³ R⁴ X, X′ R⁵ mp, ° C. 131* CH₃ CH₃ H Br, H iC₃H₇ 124-125*Hydrochloride salt

TABLE 5

Ex. R¹ R³ R⁴ X, X′ R⁵ mp, ° C. 132* CH₃ CH₃ CH₂CH₃ Br, H iC₃H₇ 144-145*Hydrochloride salt

TABLE 6

Synth. Ex. Ex. R¹ R³ R⁴ X, X′ R⁵ mp, ° C. 133 CH₃ CH₃ Et Br, H iC₃H₇oil, MS 134 23 CH₃ morpholino Et Br, H iC₃H₇ oil, MS 134* CH₃ morpholinoEt Br, H iC₃H₇  59-63 135 CH₃ thiomorpholino Et I, H iC₃H₇ oil, MS 136CH₃ morpholino Et I, H iC₃H₇ oil, MS 137 CH₃ piperidinyl Et I, H iC₃H₇oil, MS 232 CH₃ N′N-diethyl Et Br, H iC₃H₇ oil, MS 233 Cl Cl Et Br, HiC₃H₇ oil, MS 234 OCH₃ OCH₃ Et Br, H iC₃H₇ oil, MS 235 Cl Cl Et I, HiC₃H₇ oil, MS 236 CH₃ imidazolino Et Br, H iC₃H₇ >200 237 CH₃ morpholinoEt Br, CH₃O CH₃O  90-95 238 CH₃ N(CH₃)₂ Et Br, CH₃O CH₃O  65-58 239 CH₃morpholino Et CH₃O, CH₃O CH₃O oil, MS 240 CH₃ N(CH₃)₂ Et Br, H iC₃H₇ 72-75 241 CH₃ thiazolidino Et Br, H iC₃H₇  70-72 242* 29 CH₃ benzyloxyEt Br, H iC₃H₇  89-90 243 CH₃ phenyloxy Et Br, H iC₃H₇ 140-142 244 CH₃4-ethylcarboxypiperizine Et Br, CH₃O CH₃O  65-70 245 CH₃4-carboxypiperizine Et Br, CH₃O CH₃O  95-100 246 CH₃ HC(CO₂Et)₂ Et Br, HiC₃H₇ oil, MS 247 CH₃ PhCHCN Et Br, CH₃O CH₃O  50-52 248 CH₃ morpholinoiC₃H₇O Br, CH₃, O CH₃O oil, MS 249* 30 Cl Cl Et I, H CH(CH₃)₂OH oil, MS250 CH₃ Cl C₂H₅ Br, H iC₃H₇ oil, MS *Hydrochloride salt

TABLE 7

Synth. X′, Ex. Ex. R¹ R² R⁴ X R⁵ R⁶ mp, ° C. 251 62 CH₃ CH₃ Et Br, OMeBr 133-138 OMe 252 CH₃ CH₃ H H, OMe Br 179-181 OMe 253 61 CH₃ CH₃ Et H,OMe Br 143-145 OMe

TABLE 8

Synth. Ex. Ex. R¹ R³ R³⁰ X X′ R⁵ mp, ° C. 254 64 CH₃ CH₃ CN Br H i-Pr105.8 313 CH₃ CH₃ CN I H i-Pr 314 CH₃ CH₃ CN Br 6-CH₃ i-Pr 315 CH₃—morpholino CN I 6-CH₃ i-Pr 316 CH₃ Cl CN I H 1-methoxy ethyl 317 CH₃ PhCN I H 1-methoxy ethyl 318 CH₃ CH₃ CN Cl H 1-methoxy ethyl 319 CH₃ CH₃CN I H 1-methoxy ethyl 320 CH₃ CH₃ CN Br H 1-methoxy ethyl 321 CH₃—morpholino CN I CH₃ OCH₃ 255 74 CH₃ Cl CN Br H i-Pr 179.2 256 66 CH₃ PhCN Br H i-Pr oil 322 CH₃ Ph CN —SCH₃ H i-Pr 323 CH₃ CH₃ H Cl OCH₃ i-Pr257 65 CH₃ CH₃ H Br H i-Pr MS 343.08 324 CH₃ CH₃ H —SCH₃ H i-Pr 258 68CH₃ CH₃ CN Br OCH₃ OCH₃ MS 388.0 325 CH₃ —morpholino H I 6-OCH₃ i-Pr 25975 CH₃ Cl H Br H i-Pr MS 363.0 326 CH₃ Ph H I H 1-methoxy ethyl 260 69CH₃ CH₃ H Br OCH₃ OCH₃ MS 360.9 327 CH₃ CH₃ H I H 1-methoxy ethyl 328CH₃ CH₃ H Br H 1-methoxy ethyl 329 CH₃ —morpholino H I 6-CH₃ OCH₃ 330CH₃ Cl H I 6-CH₃ i-Pr 261 67 CH₃ Ph H Br H i-Pr MS 405.1 331 CH₃ —NHEt HBr H i-Pr 332 CH₃ —NHC(═O)CH₃ H Br H i-Pr 333 CH₃ OCH₃ H Br H i-Pr 334CH₃ —OCH₂Ph H Br H i-Pr 335 CH₃ CH₂OPh H Br H i-Pr 336 CH₃2-thiophenylmethoxy H Br H i-Pr 337 CH₃ —OCH(OH)Ph H Br H i-Pr 338 CH₃—n-propoxy H Br H i-Pr 339 CH₃ —C(═O)N(Me)₂ H Br H i-Pr 340 CH₃ —NHCH₂PhH Br H i-Pr 262 70 Cl CH₃ CN Br H i-Pr 123.8 341 N—Me₂ CH₃ H Br H i-Pr342 CH₃ —CH₂OCH₃ H Br H i-Pr 263 71 Cl CH₃ H Br H i-Pr MS 363.0 343 CH₃CH₃ Et Br H i-Pr 344 CH₃ CH₃ —CCH Br H i-Pr

TABLE 9

Ex. R¹ R³ X X′ R⁵ 345 CH₃ CH₃ Br H i-Pr 346 CH₃ CH₃ I H i-Pr 347 CH₃ CH₃Br 6-OCH₃ OCH₃ 348 CH₃ —morpholino I 6-CH₃ i-Pr 349 CH₃ Ph Br H i-Pr 350CH₃ CH₃ SMe H i-Pr

TABLE 10

Ex. R¹ R³ R³⁰ X X′ R⁵ 351 CH₃ CH₃ H Br H i-Pr 352 CH₃ CH₃ H I H i-Pr 353CH₃ —morpholino CN Br H i-Pr 354 CH₃ Ph CN Br H i-Pr 355 CH₃ CH₃ H SMe Hi-Pr

TABLE 11

Synth. ms Ex. Ex. R⁵ R⁴ R³ X Z K L (m + H) 264* CH₃ ethyl CH₃ Br CH CHCH 321 265* OCH₃ ethyl CH₃ Br CH CH N 337 266* OCH₃ ethyl CH₃ H CH CH N259 267* OCH₃ ethyl CH₃ Br N CH N 409 356 i-Pr ethyl CH₃ Br N N N 357i-Pr allyl CH₃ Br N N N 358 i-Pr allyl CH₃ Br CH N N 359 i-Pr ethyl CH₃Br CH N N 360 i-Pr ethyl morpholino Br N N N 361 i-Pr allyl morpholinoBr N N N 362 i-Pr allyl morpholino Br CH N N 363 i-Pr ethyl morphoiinoBr CH N N 364 OCH₃ ethyl CH₃ Br N N N 365 OCH₃ allyl CH₃ Br N N N 366OCH₃ allyl CH₃ Br CH N N 367 OCH₃ ethyl CH₃ Br CH N N 368 OCH₃ ethylmorpholino Br N N N 369 OCH₃ allyl morpholino Br N N N 370 OCH₃ allylmorpholino Br CH N N 371 OCH₃ ethyl morpholino Br CH N N 372 OCH₃ ethylCH₃ OCH₃ N N N 373 OCH₃ allyl CH₃ OCH₃ N N N 374 105 OCH₃ allyl CH₃ OCH₃CH N N 290 375 OCH₃ ethyl CH₃ OCH₃ CH N N 376 OCH₃ ethyl morpholino OCH₃N N N 377 OCH₃ allyl morpholino OCH₃ N N N 378 OCH₃ allyl morpholinoOCH₃ CH N N 379 OCH₃ ethyl morpholino OCH₃ CH N N 380 OCH₃ ethyl OCH₃OCH₃ N N N 381 OCH₃ allyl OCH₃ OCH₃ N N N 382 OCH₃ allyl OCH₃ OCH₃ CH NN 383 OCH₃ ethyl OCH₃ OCH₃ CH N N 384 OCH₃ ethyl OCH₂CH₃ OCH₃ N N N 385OCH₃ allyl OCH₂CH₃ OCH₃ N N N 386 OCH₃ allyl OCH₂CH₃ OCH₃ CH N N 387OCH₃ ethyl OCH₂CH₃ OCH₃ CH N N *Hydrochloride salt

TABLE 12

Ex. R¹ R³ R³⁰ X X′ R⁵ 388 CH₃ CH₃ CN Br H i-Pr 389 CH₃ CH₃ CN I H i-Pr390 CH₃ CH₃ CN Br 6-CH₃ i-Pr 391 CH₃ -morpholino CN I 6-CH₃ i-Pr 392 CH₃Cl CN I H 1-methoxy ethyl 393 CH₃ Ph CN I H 1-methoxy ethyl 394 CH₃ CH₃CN Cl H 1-methoxy ethyl 395 CH₃ CH₃ CN I H 1-methoxy ethyl 396 CH₃ CH₃CN Br H 1-methoxy ethyl 397 CH₃ -morpholino CN I CH₃ OCH₃ 398 CH₃ Cl CNBr H i-Pr 399 CH₃ Ph CN Br H i-Pr 400 CH₃ Ph CN —SCH₃ H i-Pr 401 CH₃ CH₃H Cl OCH₃ i-Pr 402 CH₃ CH₃ H Br H i-Pr 403 CH₃ CH₃ H —SCH₃ H i-Pr 404CH₃ CH₃ CN Br OCH₃ OCH₃ 405 CH₃ -morpholino H I 6-OCH₃ i-Pr 406 CH₃ Cl HBr H i-Pr 407 CH₃ Ph H I H 1-methoxy ethyl 408 CH₃ CH₃ H Br OCH₃ OCH₃409 CH₃ CH₃ H I H 1-methoxy ethyl 410 CH₃ CH₃ H Br H 1-methoxy ethyl 411CH₃ -morpholino H I 6-CH₃ OCH₃ 412 CH₃ Cl H I 6-CH₃ i-Pr 413 CH₃ Ph H BrH i-Pr 414 CH₃ —NHEt H Br H i-Pr 415 CH₃ —NHC(═O)CH₃ H Br H i-Pr 416 CH₃OCH₃ H Br H i-Pr 417 CH₃ —OCH₂Ph H Br H i-Pr 418 CH₃ CH₂OPh H Br H i-Pr419 CH₃ 2-thiophenyl methoxy H Br H i-Pr 420 CH₃ OCH(OH)Ph H Br H i-Pr421 CH₃ —n-propoxy H Br H i-Pr 422 CH₃ —C(═O)N(Me) H Br H i-Pr 423 CH₃—NHCH₂Ph H Br H i-Pr 424 CH₃ CH₃ CN Br H i-Pr 425 N—Me₂ CH₃ H Br H i-Pr426 CH₃ —CH₂OCH₃ H Br H i-Pr 427 Cl CH₃ H Br H i-Pr 428 CH₃ CH₃ Et Br Hi-Pr 429 CH₃ CH₃ —CCH Br H i-Pr

TABLE 13

Ex. R¹ R³ R³⁰ X X′ R⁵ 430 CH₃ CH₃ CN Br H i-Pr 431 CH₃ CH₃ CN I H i-Pr432 CH₃ CH₃ CN Br 6-CH₃ i-Pr 433 CH₃ -morpholino CN I 6-CH₃ i-Pr 434 CH₃Cl CN I H 1-methoxy ethyl 435 CH₃ Ph CN I H 1-methoxy ethyl 436 CH₃ CH₃CN Cl H 1-methoxy ethyl 437 CH₃ CH₃ CN I H 1-methoxy ethyl 438 CH₃ CH₃CN Br H 1-methoxy ethyl 439 CH₃ -morpholino CN I CH₃ OCH₃ 440 CH₃ Cl CNBr H i-Pr 441 CH₃ Ph CN Br H i-Pr 442 CH₃ Ph CN —SCH₃ H i-Pr 443 CH₃ CH₃H Cl OCH₃ i-Pr 444 CH₃ CH₃ H Br H i-Pr 445 CH₃ CH₃ H —SCH₃ H i-Pr 446CH₃ CH₃ CN Br OCH₃ OCH₃ 447 CH₃ -morpholino H I 6-OCH₃ i-Pr 448 CH₃ Cl HBr H i-Pr 449 CH₃ Ph H I H 1-methoxy ethyl 450 CH₃ CH₃ H Br OCH₃ OCH₃451 CH₃ CH₃ H I H 1-methoxy ethyl 452 CH₃ CH₃ H Br H 1-methoxy ethyl 453CH₃ -morpholino H I 6-CH₃ OCH₃ 454 CH₃ Cl H I 6-CH₃ i-Pr 455 CH₃ Ph H BrH i-Pr 456 CH₃ —NHEt H Br H i-Pr 457 CH₃ —NHC(═O)CH₃ H Br H i-Pr 458 CH₃OCH₃ H Br H i-Pr 459 CH₃ —OCH₂Ph H Br H i-Pr 460 CH₃ CH₂OPh H Br H i-Pr461 CH₃ 2-thiophenyl methoxy H Br H i-Pr 462 CH₃ OCH(OH)Ph H Br H i-Pr463 CH₃ —n-propoxy H Br H i-Pr 464 CH₃ —C(═O)N(Me)₂ H Br H i-Pr 465 CH₃—NHCH₂Ph H Br H i-Pr 466 Cl CH₃ CN Br H i-Pr 467 N—Me₂ CH₃ H Br H i-Pr468 CH₃ —CH₂OCH₃ H Br H i-Pr 469 Cl CH₃ H Br H i-Pr 470 CH₃ CH₃ Et Br Hi-Pr 471 CH₃ CH₃ —CCH Br H i-Pr

TABLE 14

Ex. R¹ R³ R³⁰ X X′ R⁵ 472 CH₃ CH₃ CN Br H i-Pr 473 CH₃ CH₃ CN I H i-Pr474 CH₃ CH₃ CN Br 6-CH₃ i-Pr 475 CH₃ -morpholino CN I 6-CH₃ i-Pr 476 CH₃Cl CN I H 1-methoxy ethyl 477 CH₃ Ph CN I H 1-methoxy ethyl 478 CH₃ CH₃CN Cl H 1-methoxy ethyl 479 CH₃ CH₃ CN I H 1-methoxy ethyl 480 CH₃ CH₃CN Br H 1-methoxy ethyl 481 CH₃ -morpholino CN I CH₃ OCH₃ 482 CH₃ Cl CNBr H i-Pr 483 CH₃ Ph CN Br H i-Pr 484 CH₃ Ph CN —SCH₃ H i-Pr 485 CH₃ CH₃H Cl OCH₃ i-Pr 486 CH₃ CH₃ H Br H i-Pr 487 CH₃ CH₃ H —SCH₃ H i-Pr 488CH₃ CH₃ CN Br OCH₃ OCH₃ 489 CH₃ -morpholino H I 6-OCH₃ i-Pr 490 CH₃ Cl HBr H i-Pr 491 CH₃ Ph H I H 1-methoxy ethyl 492 CH₃ CH₃ H Br OCH₃ OCH₃493 CH₃ CH₃ H I H 1-methoxy ethyl 494 CH₃ CH₃ H Br H 1-methoxy ethyl 495CH₃ -morpholino H I 6-CH₃ OCH₃ 496 CH₃ Cl H I 6-CH₃ i-Pr 497 CH₃ Ph H BrH i-Pr 498 CH₃ —NHEt H Br H i-Pr 499 CH₃ —NHC(═O)CH₃ H Br H i-Pr 500 CH₃OCH₃ H Br H i-Pr 501 CH₃ —OCH₂Ph H Br H i-Pr 502 CH₃ CH₂OPh H Br H i-Pr503 CH₃ 2-thiophenyl methoxy H Br H i-Pr 504 CH₃ OCH(OH)Ph H Br H i-Pr505 CH₃ -n-propoxy H Br H i-Pr 506 CH₃ C(═O)N(Me)₂ H Br H i-Pr 507 CH₃—NHCH₂Ph H Br H i-Pr 508 Cl CH₃ CN Br H i-Pr 509 N—Me₂ CH₃ H Br H i-Pr510 CH₃ —CH₂OCH₃ H Br H i-Pr 511 Cl CH₃ H Br H i-Pr 512 CH₃ CH₃ Et Br Hi-Pr 513 CH₃ CH₃ —CCH Br H i-Pr

TABLE 15

Synth. Ex. Ex. R¹ R³ X X′ R⁵ Mp (° C.) 514 CH₃ CH₃ Br H i-Pr 515 CH₃ CH₃I H i-Pr 516 CH₃ CH₃ Br 6-OCH₃ OCH₃ 517 CH₃ -morpholino I 6-CH₃ i-Pr 518CH₃ Ph Br H i-Pr 519 CH₃ CH₃ SMe H i-Pr 520 101 CH₃ Cl Br H i-Pr  49-52521 CH₃ CH₃ Br H i-Pr 522 CH₃ CH₃ I H i-Pr 523 CH₃ CH₃ Br 6-OCH₃ OCH₃524 CH₃ -morpholino I 6-CH₃ i-Pr 525 CH₃ Ph Br H i-Pr 526 CH₃ CH₃ SMe Hi-Pr 527 102 CH₃ -morpholino Br H i-Pr 132-135 528 CH₂CH₃ CH₃ Br H i-Pr529 CH₂CH₃ CH₃ I H i-Pr 530 CH₂CH₃ CH₃ Br 6-OCH₃ OCH₃ 531 CH₂CH₃-morpholino I 6-CH₃ i-Pr 532 CH₂CH₃ Ph Br H i-Pr 533 CH₂CH₃ CH₃ SMe Hi-Pr 534 CH₂CH₃ Cl Br H i-Pr 535 CH₂CH₃ CH Br H i-Pr 536 CH₂CH₃ CH₃ I Hi-Pr 537 CH₂CH₃ CH₃ Br 6-OCH₃ OCH₃ 538 CH₂CH₃ -morpholino I 6-CH₃ i-Pr539 CH₂CH₃ Ph Br H i-Pr 540 CH₂CH₃ CH₃ SMe H i-Pr 541 CH₂CH₃ -morpholinoBr H i-Pr

TABLE 16

Synth. Ex. Ex. R¹ R³ X X′ R⁵ Mp (° C.) 542 CH₃ CH₃ Br H i-Pr 543 CH₃ CH₃I H i-Pr 544 CH₃ CH₃ Br 6-OCH₃ OCH₃ 545 CH₃ -morpholino I 6-CH₃ i-Pr 546CH₃ Ph Br H i-Pr 547 CH₃ CH₃ SMe H i-Pr 548 103 CH₃ Cl Br H i-Pr MS 368549 CH₃ CH₃ Br H i-Pr 550 CH₃ CH₃ I H i-Pr 551 CH₃ CH₃ Br 6-OCH₃ OCH₃552 CH₃ -morpholino I 6-CH₃ i-Pr 553 CH₃ Ph Br H i-Pr 554 CH₃ CH₃ SMe Hi-Pr 555 104 CH₃ -morpholino Br H i-Pr 145-148 556 CH₂CH₃ CH₃ Br H i-Pr557 CH₂CH₃ CH₃ I H i-Pr 558 CH₂CH₃ CH₃ Br 6-OCH₃ OCH₃ 559 CH₂CH₃-morpholino I 6-CH₃ i-Pr 560 CH₂CH₃ Ph Br H i-Pr 561 CH₂CH₃ CH₃ SMe Hi-Pr 562 CH₂CH₃ Cl Br H i-Pr 563 CH₂CH₃ CH₃ Br H i-Pr 564 CH₂CH₃ CH₃ I Hi-Pr 565 CH₂CH₃ CH₃ Br 6-OCH₃ OCH₃ 566 CH₂CH₃ -morpholino I 6-CH₃ i-Pr567 CH₂CH₃ Ph Br H i-Pr 568 CH₂CH₃ CH₃ SMe H i-Pr 569 CH₂CH₃ -morpholinoBr H i-Pr

Utility

In vitro Receptor Binding Assay

Tissue Preparation: Male Sprague Dawley rats (180-200 g) were sacrificedby decapitation and the cortex was dissected on ice, frozen whole inliquid nitrogen and stored at −70° C. until use. On the day of assay,frozen tissue was weighed and homogenized in 20 volumes of ice coldbuffer containing 50 mM Tris, 10 mM MgCl₂, 2 mM EGTA, pH 7.0 at 22° C.using a Polytron (Brinkmann Instruments, Westbury, N.Y.; setting 6) for20 s. The homogenate was centrifuged at 48,000× g for 10 min at 4° C.The supernatant was discarded, and the pellet was re-homogenized in thesame volume of buffer and centrifuged at 48,000× g for 10 min at 4° C.The resulting pellet was resuspended in the above buffer to a finalconcentration of 20-40 mg original wet weight/mL and used in the assaysdescribed below. Protein determinations were performed according to themethod of Lowry (Lowry et al., J. Biol. Chem. 193:265 (1951)) usingbovine serum albumin as a standard.

CRF Receptor Binding: Receptor binding assays were carried outessentially as described by E. B. De Souza, J. Neurosci. 7:88 (1987).

Saturation Curve Analysis

In saturation studies, 100 μl ¹²⁵I-ovine CRF (50 pM-10 nM finalconcentration), 100 μl of assay buffer (with or without 1 mM r/hCRFfinal concentration, to define the non-specific binding) and 100 μl ofmembrane suspension (as described above) were added in sequence to 1.5mL polypropylene microfuge tubes for a final volume of 300 μl. Allassays were carried out at equilibrium for 2 h at 22° C. as described byE. B. De Souza, J. Neurosci. 7:88 (1987). The reaction was terminated bycentrifugation of the tubes in a Beckman microfuge for 5 min at 12,000×g. Aliquots of the supernatant were collected to determine the “free”radioligand concentration. The remaining supernatant was aspirated andthe pellets washed gently with ice-cold PBS plus 0.01% Triton X-100;centrifuged again and monitored for bound radioactivity as describedabove. Data from saturation curves were analyzed using the non-linearleast-squares curve-fitting program LIGAND (P. J. Munson and D. Rodbard,Anal. Biochem. 107:220 (1980)). This program has the distinct advantageof fitting the raw experimental data on an untransformed coordinatesystem where errors are most likely to be normally distributed anduncorrelated with the independent variable. LIGAND does not expect thenon-specific binding to be defined arbitrarily by the investigator,rather it estimates the value as an independent variable from the entiredata set. The parameters for the affinity constants (K_(D)) and receptordensities (B_(max)) are also provided along with statistics on thegeneral “fit” of the estimated parameters to the raw data. This programalso offers the versatility of analyzing multiple curves simultaneously,thus improving the reliability of the data analysis and hence thevalidity of the final estimated parameters for any saturationexperiment.

Competition Curve Analysis

In competition studies, 100 μl [¹²⁵I] ovine CRF ([¹²⁵I] CRF; finalconcentration 200-300 pM) was incubated along with 100 μl buffer (in thepresence of varying concentrations of competing ligands, typically 1 pMto 10 mM) and 100 μl of membrane suspension as prepared above to give atotal reaction volume of 300 μl. The reaction was initiated by theaddition of membrane homogenates, allowed to proceed to equilibrium for2 h at 22° C. and was terminated by centrifugation (12,000× g) in aBeckman microfuge to separate the bound radioligand from freeradioligand. The resulting pellets were surface washed twice bycentrifugation with 1 mL of ice-cold phosphate buffered saline and 0.01%Triton X-100; the supernatants discarded and the pellets monitored forradioactivity at approximately 80% efficiency. The level of non-specificbinding was defined in the presence of 1 mM unlabeled rat/humanCRF(r/hCRF). Data from competition curves were analyzed by the programLIGAND. For each competition curve, estimates of the affinity of theradiolabeled ligand for the CRF receptor ([¹²⁵I]CRF) were obtained inindependent saturation experiments and these estimates were constrainedduring the analysis of the apparent inhibitory constants (K_(i)) for thepeptides tested. Routinely, the data were analyzed using a one- andtwo-site model comparing the “goodness of fit” between the models inorder to accurately determine the K_(i). Statistical analyses providedby LIGAND allowed the determination of whether a single-site ormultiple-site model should be used. For both peptides (α-helical CRF₉₋₄₁and d-PheCRF₁₂₋₄₁), as well as for all compounds of this invention, datawere fit significantly to a single site model; a two-site model waseither not possible or did not significantly improve the fit of theestimated parameters to the data.

The results of the in vitro testing of the compounds of the inventionare shown in Table 17. It was found, for a representative number ofcompounds of the invention, that either form of the compound, be it thefree-base or the hydrochloride salt, produced essentially the sameinhibition value in the binding assay.

A compound is considered to be active if it has an K_(i) value of lessthan about 10000 nM for the inhibition of CRF. In Table 17; the K_(i)values were determined using the assay conditions described above. TheK_(i) values are indicated as follows: +++=<500 nM; ++=501-2000 nM;+=2001-10000 nM.

TABLE 17 Example Synth. Inhibition No. Ex. K_(i) (nM) 1 1 ++ 2 ++ 3 ++ 42 +++ 5 ++ 6 ++ 7 +++ 8 +++ 9 3 +++ 10 +++ 11 +++ 12 ++ 13 +++ 14 ++ 15+++ 16 4 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 5 +++ 22 ++ 23 +++ 24 ++ 25+++ 26 +++ 27 +++ 28 +++ 29 6 +++ 30 7 +++ 31 8 +++ 32 +++ 33 9 +++ 3410 +++ 37 +++ 49 12 + 50 13 +++ 51 ++ 52 + 53 + 54 + 55 +++ 56 14 +++ 5715 +++ 58 16 +++ 59 17 +++ 60 ++ 61 18 +++ 62 ++ 63 19 + 64 20 + 65 21 +66 + 68 + 69 + 70 + 71 + 72 + 73 22 +++ 74 +++ 78 + 95 ++ 130 ++ 131 +132 + 133 ++ 134 23 +++ 135 +++ 136 +++ 137 +++ 138 24 +++ 139 25 +++140 26 +++ 141 +++ 142 +++ 143 +++ 145 + 146 + 147 +++ 148 +++ 149 +++150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++159 27 +++ 160 28 +++ 161 +++ 162 +++ 163 ++ 165 31 +++ 166 34 +++ 16732 +++ 168 35 +++ 170 36 +++ 171 38 +++ 172 39 +++ 173 40 ++ 174 41 +++175 42 ++ 176 43 +++ 177 33 ++ 178 44 +++ 179 45 + 180 46 +++ 181 47 +++182 48 +++ 183 49 + 184 ++ 185 51 +++ 186 52 +++ 187 +++ 188 54 +++ 18955 +++ 190 56 +++ 191 57 +++ 192 +++ 193 +++ 194 +++ 195 +++ 196 +++ 197++ 201 +++ 203 ++ 204 + 205 +++ 206 +++ 207 +++ 208 +++ 209 +++ 210 ++211 +++ 212 +++ 213 +++ 214 ++ 215 ++ 216 +++ 217 +++ 218 +++ 219 +++221 +++ 222 58 ++ 223 ++ 224 63 +++ 225 59 +++ 226 +++ 227 +++ 228 ++229 + 230 60 +++ 231 + 232 +++ 236 +++ 237 +++ 238 +++ 239 +++ 240 +++241 +++ 242 29 ++ 243 + 244 + 245 + 246 +++ 247 +++ 248 +++ 249 30 + 250++ 251 62 ++ 252 + 253 61 ++ 254 64 +++ 255 74 ++ 256 66 +++ 257 65 +++258 68 +++ 259 75 +++ 260 69 +++ 261 67 +++ 262 70 +++ 263 71 +++ 26477 + 265 76 +++ 266 78 ++ 267 79 +++ 268 +++ 269 +++ 270 + 271 +++ 272 +273 ++ 274 + 275 +++ 276 +++ 277 +++ 278 +++ 279 +++ 280 +++ 281 +++ 282+++ 283 + 284 +++ 285 +++ 286 +++ 287 ++ 288 +++ 289 +++ 290 +++ 291 +++292 +++ 293 +++ 294 +++ 295 +++ 296 +++ 297 80 +++ 298 82 +++ 299 83 +++300 84 +++ 301 85 +++ 302 86 +++ 303 87 +++ 304 88 +++ 305 89 +++ 307 91+++ 308 92 +++ 309 93 +++ 310 94 ++ 311 95 +++ 312 96 +++

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity was performed asdescribed by G. Battaglia et al., Synapse 1:572 (1987). Briefly, assayswere carried out at 37° C. for 10 min in 200 mL of buffer containing 100mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mMisobutylmethylxanthine (IBMX), 250 units/mL phosphocreatine kinase, 5 mMcreatine phosphate, 100 mM guanosine 5′-triphosphate, 100 nM oCRF,antagonist peptides (concentration range 10⁻⁹ to 10^(−6m)) and 0.8 mgoriginal wet weight tissue (approximately 40-60 mg protein). Reactionswere initiated by the addition of 1 mM ATP/³²P]ATP (approximately 2-4mCi/tube) and terminated by the addition of 100 mL of 50 mM Tris-HCl, 45mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recoveryof cAMP, 1 μl of [³H]cAMP (approximately 40,000 dpm) was added to eachtube prior to separation. The separation of [³²P]cAMP from [³²P]ATP wasperformed by sequential elution over Dowex and alumina columns. Recoverywas consistently greater than 80%.

Representative compounds of this invention were found to be active inthis assay. IC₅₀<10,000 nanomolar.

In Vivo Biological Assay

The in vivo activity of the compounds of the present invention can beassessed using any one of the biological assays available and acceptedwithin the art. Illustrative of these tests include the Acoustic StartleAssay, the Stair Climbing Test, and the Chronic Administration Assay.These and other models useful for the testing of compounds of thepresent invention have been outlined in C. W. Berridge and A. J. DunnBrain Research Reviews 15:71 (1990).

Compounds may be tested in any species of rodent or small mammal.Disclosure of the assays herein is not intended to limit the enablementof the invention.

The foregoing tests results demonstrate that compounds of this inventionhave utility in the treatment of imbalances associated with abnormallevels of corticotropin releasing factor in patients suffering fromdepression, affective disorders, and/or anxiety. The foregoing testsalso demonstrate that compounds of this invention have utility in thetreatment of uterine contraction disorders.

Compounds of this invention can be administered to treat saidabnormalities by means that produce contact of the active agent with theagent's site of action in the body of a mammal. The compounds can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butare generally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage administered will vary depending on the use and known factorssuch as the pharmacodynamic character of the particular agent, and itsmode and route of administration; the recipient's age, weight, andhealth; nature and extent of symptoms; kind of concurrent treatment;frequency of treatment; and desired effect. For use in the treatment ofsaid diseases or conditions, the compounds of this invention can beorally administered daily at a dosage of the active ingredient of 0.002to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg individed doses one to four times a day, or in sustained releaseformulation is effective in obtaining the desired pharmacologicaleffect.

Dosage forms (compositions) suitable for administration contain fromabout 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5 to 95% by weight based on the totalweight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets and powders; or in liquid forms such aselixirs, syrups, and/or suspensions. The compounds of this invention canalso be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and asuitable carrier, such as, but not limited to, lactose, starch,magnesium stearate, steric acid, or cellulose derivatives. Similardiluents can be used to make compressed tablets. Both tablets andcapsules can be manufactured as sustained release products to providefor continuous release of medication over a period of time. Compressedtablets can be sugar-coated or film-coated to mask any unpleasant taste,or used to protect the active ingredients from the atmosphere, or toallow selective disintegration of the tablet in the gastrointestinaltract.

Liquid dose forms for oral administration can contain coloring orflavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueousdextrose (glucose), and related sugar solutions and glycols, such aspropylene glycol or polyethylene glycol, are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents, such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or in combination, are suitable stabilizing agents. Alsoused are citric acid and its salts, and EDTA. In addition, parenteralsolutions can contain preservatives such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences”, A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of units in the form of capsules are prepared by fillingstandard two-piece hard gelatin capsules each with 100 mg of powderedactive ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesiumstearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean,cottonseed oil, or olive oil is prepared and injected by means of apositive displacement into gelatin to form soft gelatin capsulescontaining 100 mg of the active ingredient. The capsules are washed anddried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatingsmay be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents orstandards in the biochemical study of neurological function,dysfunction, and disease.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ isindependently selected, at each occurrence from the group consisting ofC₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, and C₁-C₂ haloalkyl; R³ isC₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₂ haloalkyl, nitro, NR⁶R⁷, OR⁸,S(O)_(n)R⁸, C(═O)R⁹, C(═O)NR⁶R⁷, C(═S)NR⁶R⁷, —(CHR¹⁶)_(k)NR⁶R⁷,(CH₂)_(k)OR⁸, C(═O)NR¹⁰CH(R¹¹)CO₂R¹², —C(OH)(R²⁵)(R^(25a)),—(CH₂)_(p)S(O)_(n)-alkyl, —(CHR¹⁶)R²⁵, —C(CN)(R²⁵)(R¹⁶), —C(═O)R²⁵,—CH(CO₂R¹⁶)₂, NR¹⁰C(═O)CH(R¹¹)NR¹⁰R¹², NR¹⁰CH(R¹¹)CO₂R¹²; K and L areeach independently CX′; R² is independently selected at each occurrencefrom the group consisting of hydrogen, halo, halomethyl, C₁-C₃ alkyl,and cyano; R⁴ is (CH₂)_(m)OR¹⁶, C₁-C₄ alkyl, allyl, propargyl,(CH₂)_(m)R¹³, or —(CH₂)_(m)OC(O)R¹⁶; X is halogen, S(O)₂R⁸, SR⁸,halomethyl, —(CH₂)_(p)OR⁸, cyano, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, —C(═O)R⁸, C₁-C₆alkyl, C₄-C₁₀ cycloalkylalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀alkoxy, C₃-C₆ cycloalkyl, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents; X′ isindependently selected at each occurrence from the group consisting ofhydrogen, halogen, S(O)_(n)R⁸, halomethyl, —(CHR¹⁶)_(p)OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀ alkoxy, C₃-C₆ cycloalkyl, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵ where substitutionby R¹⁸ can occur on any carbon containing substituents; R⁵ is halo,—C(═NOR¹⁶)—C₁-C₄-alkyl, C₁-C₆ alkyl, C₁-C₃ haloalkyl, C₁-C₆ alkoxy,—(CHR¹⁶)_(p)OR⁸, (CHR¹⁶)_(p)S(O)_(n)R⁸, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃-C₆cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cyano, C₃-C₆ cycloalkoxy,nitro, amino-(C₂-C₁₀)-alkyl, thio-(C₂-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or C(═O)NR¹⁴R¹⁵, where substitution by R¹⁸ can occur on anycarbon containing substituents; R⁶ and R⁷ are independently selected ateach occurrence from the group consisting of hydrogen, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, (C₄-C₁₂)-cycloalkylalkyl,—(CH₂)_(k)R¹³, (CHR¹⁶)_(p)OR⁸, —(C₁-C₆ alkyl)-aryl, phenyl, heteroaryl,—S(O)_(z)-aryl or —(C₁-C₆ alkyl)-heteroaryl, wherein the aryl orheteroaryl groups are optionally substituted with 1-3 groups selectedfrom the group consisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, amino, NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂,nitro, carboxy, CO₂(C₁-C₆ alkyl), cyano, S(O)_(z)—(C₁-C₆ alkyl); or canbe taken together to form —(CH₂)_(q)A(CH₂)_(r)—, optionally substitutedwith 0-3 R¹⁷; A is CH₂, O, NR²⁵, C(═O), S(O)_(n), N(C(═O)R¹⁷), N(R¹⁹),C(H)(NR¹⁴R¹⁵), C(H)(OR²⁰), C(H)(C(═O)R²¹), N(S(O)_(n)R²¹); R⁸ isindependently selected at each occurrence from the group consisting ofhydrogen; C₁-C₆ alkyl; —(C₄-C₁₂) cycloalkylalkyl; (CH₂)_(t)R²²; C₃-C₁₀cycloalkyl; —NR⁶R⁷; aryl; heteroaryl; —NR¹⁶(CH₂)_(n)NR⁶R⁷;—(CH₂)_(k)R²⁵; and (CH₂)_(t)heteroaryl or (CH₂)_(t)aryl, either of whichcan be optionally substituted with 1-3 groups selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino,NHC(═O)(C₁-C₆ alkyl), NH(C₁-C₆ alkyl) N(C₁-C₆ alkyl)₂, nitro, carboxy,CO₂(C₁-C₆ alkyl), cyano, and S(O)_(z)(C₁-C₆-alkyl); R⁹ is independentlyselected at each occurrence from R¹⁰, hydroxy, C₁-C₄ alkoxy, C₃-C₆cycloalkyl, C₂-C₄ alkenyl, phenyl substituted with 0-3 R¹⁸, and —(C₁-C₆alkyl)-aryl substituted with 0-3 R¹⁸; R¹⁰, R¹⁶, R²³, and R²⁴ areindependently selected at each occurrence from hydrogen or C₁-C₄ alkyl;R¹¹ is C₁-C₄ alkyl substituted with 0-3 groups chosen from thefollowing: keto, amino, sulfhydryl, hydroxyl, guanidinyl,p-hydroxyphenyl, imidazolyl, phenyl, indolyl, and indolinyl, or, whentaken together with an adjacent R¹⁰, are (CH₂)_(t); R¹² is hydrogen oran appropriate amine protecting group for nitrogen or an appropriatecarboxylic acid protecting group for carboxyl; R¹³ is independentlyselected at each occurrence from the group consisting of CN, OR¹⁹, SR¹⁹,and C₃-C₆ cycloalkyl; R¹⁴ and R¹⁵ are independently selected at eachoccurrence from the group consisting of hydrogen, C₄-C₁₀cycloalkyl-alkyl, and R¹⁹; R¹⁷ is independently selected at eachoccurrence from the group consisting of R¹⁰, C₁-C₄ alkoxy, halo, OR²³,SR²³, NR²³R²⁴, and (C₁-C₆) alkyl (C₁-C₄) alkoxy; R¹⁸ is independentlyselected at each occurrence from the group consisting of R¹⁰, hydroxy,halogen, C₁-C₂ haloalkyl, C₁-C₄ alkoxy, C(═O)R²⁴, and cyano; R¹⁹ isindependently selected at each occurrence from the group consisting ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, (CH₂)_(w)R²², and phenyl substituted with0-3 R¹⁸; R²⁰ is independently selected at each occurrence from the groupconsisting of R¹⁰, C(═O)R³¹, and C₂-C₄ alkenyl; R²¹ is independentlyselected at each occurrence from the group consisting of R¹⁰, C₁-C₄alkoxy, NR²³R²⁴, and hydroxyl; R²² is independently selected at eachoccurrence from the group consisting of cyano, OR²⁴, SR²⁴, NR²³R²⁴,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, —S(O)_(n)R³¹, and —C(═O)R²⁵; R²⁵, whichcan be optionally substituted with 0-3 R¹⁷, is independently selected ateach occurrence from the group consisting of phenyl, and pyridyl;R^(25a), which can be optionally substituted with 0-3 R¹⁷, isindependently selected at each occurrence from the group consisting of Hand R²⁵; R²⁷ is independently selected at each occurrence from the groupconsisting of C₁C₃ alkyl, C₂-C₄ alkenyl, C₂₋₄ alkynl, C₂₋₄ alkoxy, aryl,nitro, cyano, halogen, and phenyloxy; R³¹ is independently selected ateach occurrence from the group consisting of C₁-C₄ alkyl, C₃-C₇cycloalkyl, C₄-C₁₀ cycloalkyl-alkyl, and aryl-(C₁-C₄) alkyl; k, m, and rare independently selected at each occurrence from 1-4; n isindependently selected at each occurrence from 0-2; p, q, and z areindependently selected at each occurrence from 0-3; t and w areindependently selected at each occurrence from 1-6; provided that when Kand L are both CH, then (A) when R² is H and R¹ and R³ are methyl, (1)and R⁴ is methyl, then (a) R⁵ can not be C₁-C₆ alkyl when X is OH and X′is H; (b) R⁵ can not be (CHR¹⁶)_(p)NR¹⁴R¹⁵ wherein p is 0 when X and X′are —OCH₃; and (c) R⁵ can not be (CHR ¹⁶)_(p)NR¹⁴R¹⁵ when X and X′ are—OCH₂CH₃; and (2) and R⁴ is ethyl, then (a) R⁵ can not be(CHR¹⁶)_(p)NR¹⁴R¹⁵ when X and X′ are —OCH₃; (b) R⁵ can not be(CHR¹⁶)_(p)OR¹⁸ with p=0 and R¹⁸=H when X is Br and X′ is OH; and (c) R⁵can not be C1-C6 alkyl substituted with OH; or (CHR¹⁶)_(p)NR¹⁴R¹⁵wherein R¹⁶=H and p=1-3 and R¹⁴ and R¹⁵ are H or C₁-C₆ alkyl when X is—SCH₃ and X′ is H; (B) when R² is H, R⁴ is ethyl, R⁵ is iso-propyl, X isBr, X′ is H, and (1) R¹ is CH₃; then (a) R³ can not be OR⁸, CO₂R¹²,C(═O)NR⁶R⁷, (CH₂)_(k)OR₈; (CHR¹⁶)_(k)NR⁶R⁷; (2) R¹ is —CH₂CH₂CH₃ then R³can not be C₁-C₆ alkyl; further provided that when X′ is H, and K and Lare both CH, then (D) when R² is H or C₁-C₃ alkyl; R⁴ is C₁-C₄ alkyl;R⁵, X and/or X′ are OH, halo, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, amino, carbamoyl, or C₁-C₄ alkanoyl; and R¹ is C₁-C₄alkyl, then R³ can not be —NH(substituted phenyl) or —N (C₁-C₄ alkyl)(substituted phenyl) and further provided that when R³ is S(O)_(n)R⁸, R⁸is not hydrogen; and when R³ is —C(CN)(R²⁵)(R¹⁶), R²⁵ is not pyridyl andwhen R³ is S(O)_(n)R⁸, R⁸ is not H; wherein the term “heterocycle” isdefined as pyridyl, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl,indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl,4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl or octahydroisoquinolinyl, azocinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl,thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathiinyl, 2H-pyrrolyl, pyrrole, imidazolyl, pyrazolyl,isothiazolyl, isoxazole, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolizinyl, isoindole, 3H-indolyl, indolyl, 1H-indazolyl, purinyl,4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl oroxazolidinyl; wherein the term “aryl” is defined as phenyl, biphenyl ornaphthyl; and wherein the term “heteroaryl” is defined as 2-, or 3-, or4-pyridyl; 2- or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2-or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2-, or 4-, or5-oxazolyl; 2-benzoxazolyl; 2- or 4- or 5-imidazolyl; 1- or2-benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3-or 4- cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or2-quinoxalinyl ring.
 2. A compound of claim 1 wherein: R¹ is C₁-C₄alkyl; R³ is C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₂ haloalkyl, NR⁶R⁷, OR⁸,C(═O)R⁹, C(═O)NR⁶R⁷, —(CHR¹⁶)_(k)NR⁶R⁷, (CH₂)_(k)OR⁸, —(CHR¹⁶)R²⁵,substituted C₁-C₄ alkyl, substituted C₁-C₄ alkenyl, substituted C₂-C₄alkynyl, substituted C₁-C₄ alkoxy, substituted C₃-C₆ cycloalkyl orsubstituted C₁-C₄ alkylamino, where substitution by one or two R²⁷ canoccur on any carbon-containing substituent; R⁴ is C₁-C₄ alkyl, allyl, orpropargyl; X is halogen, S(O)₂R⁸, SR⁸, halomethyl, —(CH₂)_(p)OR⁸, cyano,—(CHR¹⁶)_(p)NR¹⁴R¹⁵, —C(═O)R⁸, C₁-C₆ alkyl, C₄-C₁₀ cycloalkylalkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkoxy, aryl-(C₂-C₁₀)-alkyl,C₃-C₆ cycloalkyl, aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵; X′ isindependently selected at each occurrence from the group consisting ofhydrogen, halogen except when M is N, S(O)_(n)R⁸, halomethyl,—(CHR¹⁶)_(p)OR⁸, cyano, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C(═O)R⁸, C₁-C₆ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkoxy, aryl-(C₁-C₁₀)-alkyl,C₃-C₆ cycloalkyl, aryl-(C₁-C₁₀)-alkoxy, nitro, thio-(C₁-C₁₀)-alkyl,—C(═NOR¹⁶)—C₁-C₄-alkyl, —C(═NOR¹⁶)H, or —C(═O)NR¹⁴R¹⁵; R⁵ is halo,—C(═NOR¹⁶)—C₁-C₄-alkyl, C₁-C₆ alkyl, C₁-C₃ haloalkyl, C₁-C₆ alkoxy,—(CHR¹⁶)_(p)OR⁸, (CHR¹⁶)_(p)S(O)_(n)R⁸, —(CHR¹⁶)_(p)NR¹⁴R¹⁵, C₃-C₆cycloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, cyano, C₃-C₆ cycloalkoxy,nitro, amino-(C₂-C₁₀)-alkyl, thio-(C₂-C₁₀)-alkyl, SO_(n)(R⁸), C(═O)R⁸,—C(═NOR¹⁶)H, or C(═O)NR¹⁴R¹⁵; R⁶ and R⁷ are independently selected ateach occurrence from the group consisting of hydrogen, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, (C₄-C₁₂)-cycloalkylalkyl,—(CH₂)_(k)R¹³, (CHR¹⁶)_(p)OR⁸, phenyl, or —S(O)_(z)-aryl; or can betaken together to form —(CH₂)_(q)A(CH₂)_(r)—, optionally substitutedwith 0-3 R¹⁷; R⁸ is independently selected at each occurrence from thegroup consisting of hydrogen; C₁-C₆ alkyl; —(C₄-C₁₂) cycloalkylalkyl;(CH₂)_(t)R²²; C₃-C₁₀ cycloalkyl; or —NR⁶R⁷; and R⁹ is independentlyselected at each occurrence from R¹⁰, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, orC₂-C₄ alkenyl.
 3. A compound of claim 1 selected from the groupconsisting of: N-(2,4-dimethoxyphenyl)-N-4,6-dimethyl-2-pyrimidinamine;N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-cyclohexylethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-pyrimidinamine;N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(₂-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxyethylamino)-2-pyrimidinamine;N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbonyl)-2-pyrimidinamine;methyl2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylate;2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyrimidinecarboxamide;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazinylcarbonyl)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfinyl)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfonyl)-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4(S)-(N-methyl-2′-pyrrolidinomethoxy)-6-methyl-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylsulfinyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4-thiazolidino-6-methyl-2-pyrimidinamine;N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylsulfonyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-ethylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinamine;N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(N-acetyl-N-methylamino)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-(1-methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-(N-methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-(N,N-dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-formyl-6-methyl-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6-methyl-2-pyrimidinamine;N-(2-Bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(3-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,3-Dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N-methylamino)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino)carbonyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)methyl-6-methylpyrimidinamine,hydrochloride salt;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-(methoxyphenyl)methoxymethyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5-indolylcarbonyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-fluorophenyl)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-(methoxyphenyl)-3-pyridyl-hydroxymethyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimidinamine,hydrochloride salt;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminoethyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1-methylethyl)-6-methylpyrimidinamine;2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine;and2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methylpyrimidine.4. A compound of claim 1 selected from the group consisting of:N-(2,4-dimethoxyphenyl)-N-4,6-dimethyl-2-pyrimidinamine;N-(2-bromophenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-dibromophenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-ethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-tert-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-tert-butylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-trifluoromethylphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-trifluoromethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4,6-trimethoxyphenyl)-N-methyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4,6-trimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-n-butylphenyl)-N-propyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-cyclohexylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-allyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-methoxyethyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyanomethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-cyclopropylmethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-propargyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-methoxyethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-dimethylamino-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-dimethylamino-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-dimethylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methylthiomethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,6-dibromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,4-diiodophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,6-dimethoxy-4-methylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylsulfinyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-iodo-4-methoxymethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylsulfonyl-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-ethylthio-4-(1-methylethyl)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-ethylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylsulfonyl-4-methoxyiminoethylphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-bromo-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-ethyl-2-methylthiophenyl)-N-(1-methylethyl)-4,6-dimethyl-2-pyrimidinamine;N-(4-ethyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-methylthio-4-(N-acetyl-N-methylamino)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-carboethoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-methoxy-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-cyano-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-acetyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-propionyl-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-(1-methoxyethyl)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-(N-methylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(4-(N,N-dimethylamino)-2-methylthiophenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2-Bromo-6-hydroxy-4-methoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(3-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;N-(2,3-Dibromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine;andN-(2,6-Dibromo-4-(ethoxy)phenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine.5. A compound of claim 1 selected from the group consisting of:N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4,6-diethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-formyl-piperazino)-6-methyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-trifluoromethyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(2-thiopheno)-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(N-methyl-2-hydroxyethylamino)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-2,4-dimethoxy-6-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(1-piperidinylcarbonyl)-2-pyrimidinamine;methyl2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-6-methyl-4-pyrimidinecarboxylate;2-((2-bromo-4-(1-methylethyl)phenyl)ethylamino)-N-cyclohexyl-6-methyl-4-pyrimidinecarboxamide;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazinylcarbonyl)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(thiomethyl)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfinyl)-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(methylsulfonyl)-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-formyl-6-methyl-2-pyrimidinamine;N-(2-Bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-hydroxyethoxymethyl-6-methyl-2-pyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(N-(2-furylmethyl)-N-methylamino)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-((4,4-ethylenedioxypiperidino)carbonyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-oxopiperidino)methyl-6-methylpyrimidinamine,hydrochloride salt;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidinamine;N-(₂-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-(methoxyphenyl)methoxymethyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidinamine;N-(₂-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(5-indolylcarbonyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-fluorophenyl)carbonyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-acetyl-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(hydroxy-3-pyridyl-methyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(4-(methoxyphenyl)-3-pyridyl-hydroxymethyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyrazolyl)-6-methylpyrimidinamine,hydrochloride salt;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-aminoethyl)-6-methylpyrimidinamine;N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-(4-tetrazolyl)-1-methylethyl)-6-methylpyrimidinamine;2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine;and2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methylpyrimidine.6. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.7. A method of treating affective disorders, anxiety, or depression inmammals in need of such treatment comprising administering to themammals a therapeutically effective amount of a compound of claim 1.